Heterocyclic Carboxamides For Use As Thrombin Inhibitors

ABSTRACT

This invention relates to novel pharmaceutically useful compounds of formula (I), in particular compounds that are competitive inhibitors of trypsin-like serine proteases, especially thrombin, their use as medicaments, pharmaceutical compositions containing them and synthetic routes to their production. Formula (I)

FIELD OF THE INVENTION

This invention relates to novel pharmaceutically useful compounds, inparticular compounds that are competitive inhibitors of trypsin-likeserine proteases, especially thrombin, their use as medicaments,pharmaceutical compositions containing them and synthetic routes totheir production.

BACKGROUND

Blood coagulation is the key process involved in both haemostasis (i.e.the prevention of blood loss from a damaged vessel) and thrombosis (i.e.the formation of a blood clot in a blood vessel, sometimes leading tovessel obstruction).

Coagulation is the result of a complex series of enzymatic reactions.One of the ultimate steps in this series of reactions is the conversionof the proenzyme prothrombin to the active enzyme thrombin.

Thrombin is known to play a central role in coagulation. It activatesplatelets, leading to platelet aggregation, converts fibrinogen intofibrin monomers, which polymerise spontaneously into fibrin polymers,and activates factor XIII, which in turn crosslinks the polymers to forminsoluble fibrin. Furthermore, thrombin activates factor V, factor VIIIand factor XI leading to a “positive feedback” generation of thrombinfrom prothrombin.

By inhibiting the aggregation of platelets and the formation andcrosslinking of fibrin, effective inhibitors of thrombin would beexpected to exhibit antithrombotic activity. In addition, antithromboticactivity would be expected to be enhanced by effective inhibition of thepositive feedback mechanism. Indeed, the convincing antithromboticeffects of a thrombin inhibitor in man have been described by S.Schulman et al. in N. Engl. J. Med. 349, 1713-1721 (2003), L. Wallentinet al. in Lancet 362, 789-97 (2003) and H.-C. Diener et al. inCerebrovasc. Dis. 21, 279-293 (2006).

The early development of low molecular weight inhibitors of thrombin hasbeen described by Claesson in Blood Coagul. Fibrinol. 5, 411 (1994).

Blombäck et al. (in J. Clin. Lab. Invest. 24, suppl. 107, 59 (1969))reported thrombin inhibitors based on the amino acid sequence situatedaround the cleavage site for the fibrinogen Aα chain. Of the amino acidsequences discussed, these authors suggested the tripeptide sequencePhe-Val-Arg (P9-P2-P1, hereinafter referred to as the P3-P2-P1 sequence)would be the most effective inhibitor.

Thrombin inhibitors based (at the P1-position of the molecule) upon the2-heteroaromatic substituted 1-yl-benzylamide structural unit aredisclosed in U.S. Pat. No. 7,144,899 and WO2004032834.

Thrombin inhibitors based (at the P2-position of the molecule) upon the1-acetyl-pyrrolidine-2-carboxylic acid amide,1-acetyl-piperidine-2-carboxylic acid amide or1-acetyl-azepane-2-carboxylic acid amide structural units are disclosedin U.S. Pat. No. 7,144,899.

Thrombin inhibitors based (at the P2-position of the molecule) upon the1-acetyl-pyrrolidine-2-carboxylic acid amide or1-acetyl-dihydropyrrole-2-carboxylic acid amide structural units aredisclosed in U.S. Pat. No. 6,515,011 and WO2004032834.

Thrombin inhibitors based (at the P2-position of the molecule) upon the1-acetyl-azepane-2-carboxylic acid amide structural unit are disclosedin U.S. Pat. No. 6,528,503.

Thrombin inhibitors based (at the P2-position of the molecule) upon theaza-bicyclo[3.1.0]hexane-1-carboxylic acid amide structural unit aredisclosed in U.S. Pat. No. 6,288,077.

Thrombin inhibitors based (at the P2-position of the molecule) upon the1,3-thiazolidine-2-carboxylic acid amide, 1,3-thiazolidine-4-carboxylicacid amide, pyrazolidine-3-carboxylic acid amide and4,5-dihydro-1H-pyrazole-5-carboxylic acid amide structural units aredisclosed in U.S. Pat. No. 6,740,647 and also described by Lange et al.in Bioorganic & Medicinal Chemistry Letters 16, 2648-2653 (2006).

Quantitative structure activity relationship studies of arylheterocycle-based thrombin inhibitors are described by Roy et al. inEuropean Journal of Medicinal Chemistry 41, 1339-1346 (2006).

Thrombin inhibitors based (at the P2-position of the molecule) upon4-fluoroprolines are described by Staas et al. in Bioorganic & MedicinalChemistry 14, 6900-6916 (2006).

Thrombin inhibitors based (at the P2-position of the molecule) uponpyrazinones carrying various aryl-heterocycles at the P1-position of themolecule are described by Young et al. in Journal of Medicinal Chemistry47, 2995-3008 (2004).

There remains a need for effective inhibitors of trypsin-like serineproteases, such as thrombin. There is also a need for compounds thathave a favourable pharmacokinetic profile. Such compounds would beexpected to be useful as anticoagulants and therefore in the therapeutictreatment of thrombosis and related disorders.

DISCLOSURE OF THE INVENTION

In one aspect of the present invention there is provided a compound offormula (I)

wherein

X is N, O or NH;

Y is CH₂ when X is O or NH, with X and Y connected via a single bond,or, alternatively,

Y is CH when X is N, with X and Y connected via a double bond;

R¹ is a 5-membered heteroaryl ring containing 2, 3 or 4 heteroatoms,selected from N, O and S, wherein at least 2 heteroatoms are N, and 0 or1 heteroatoms are O or S, wherein said 5-membered heteroaryl ring issubstituted, at any carbon ring atom, by 0, 1 or 2 substituentsindependently selected from C₁₋₆ alkyl and a 6-membered heteroaryl ringcontaining 1 or 2 nitrogen atoms, wherein said 6-membered heteroarylring is substituted, at any carbon ring atom, by 0, 1, 2 or 3substituents independently selected from C₁₋₆ alkyl;

R² is H, halogen, cyano, C₁₋₆ alkyl or C₁₋₆ alkoxy, wherein said C₁₋₆alkyl or C₁₋₆ alkoxy is substituted by 0, 1, 2, 3, 4 or 5 halogen;

G represents

wherein

R³ is H, R⁵, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₃₋₆ cycloalkyl,wherein each of said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₃₋₆cycloalkyl are independently substituted by 0, 1, 2, 3, 4 or 5substituents selected from halogen and 0, 1 or 2 substituents selectedfrom OH, oxo, cyano, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₄₋₇ cycloalkenyl, cycloheteroalkyl, R⁵ and R⁶;

R⁵ is phenyl,

a 5 or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatomsindependently selected from O, S and N,

a 4-, 5- or 6-membered cycloheteroalkyl ring containing 1 or 2heteroatoms independently selected from O, S and N or

a phenyl-fused 5- or 6-membered cycloheteroalkyl ring containing 1 or 2heteroatoms independently selected from O, S and N, wherein said phenyl,said heteroaromatic ring, said cycloheteroalkyl ring and saidphenyl-fused cycloheteroalkyl ring are substituted, at any carbon ringatom, by 0, 1, 2, 3, 4 or 5 substituents independently selected fromCOOH, OH, halogen, CF₃, CHF₂, CH₂F, cyano, C₁₋₆ alkyl, R⁶ and SO₂R⁷;

R⁶ is C₁₋₆ alkoxy, wherein said C₁₋₆ alkoxy is substituted by 0, 1, 2,3, 4 or 5 halogen;

R⁷ is C₁₋₆ alkyl;

R⁴ is OH, OC(O)R⁷, OC(O)R⁸ or NHR⁹;

R⁸ is phenyl, wherein said phenyl is substituted by 0, 1, 2, 3, 4 or 5substituents independently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,F, CF₃, CHF₂ and CH₂F or

C₁₋₄ alkyl, wherein said C₁₋₄ alkyl is substituted by 0, 1, 2 or 3substituents independently selected from methyl and ethyl and 0 or 1substituents selected from phenyl, wherein said phenyl is substituted by0, 1, 2, 3, 4 or 5 substituents independently selected from C₁₋₄ alkyl,C₁₋₄ alkoxy, cyano F, CF₃, CHF₂, CH₂F and OC(O)R⁷;

R⁹ is H, COOR⁷ or SO₂R⁷ wherein said R⁷ is substituted by 0, 1, 2 or 3substituents independently selected from OH, halogen, cyano, R⁶ and C₃₋₇cycloalkyl;

Q is O, CH₂ or S(O)_(n);

W is C or N;

n is independently 0, 1 or 2;

t is independently 0, 1 or 2;

u is independently 0 or 1;

R¹⁰ is 0, 1, 2, 3, 4 or 5 substituents selected from halogen, OH, oxo,cyano, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, R⁵ and R⁶, wherein said C₁₋₄ alkylis substituted by 0 or 1 substituent selected from R⁵, NH₂, NH(C₁₋₄alkyl) or N(C₁₋₄ alkyl)₂; and

R¹¹ is 0, 1, 2, 3, 4 or 5 substituents selected from halogen, OH, cyano,C₁₋₄ alkyl, C₃₋₆ cycloalkyl, R⁵ and R⁶, wherein said C₁₋₄ alkyl issubstituted by 0 or 1 substituent selected from R⁵, NH₂, NH(C₁₋₄ alkyl)or N(C₁₋₄ alkyl)₂;

or a pharmaceutically acceptable salt or an enantiomer or apharmaceutically acceptable salt of said enantiomer.

The compounds of formula (I) have chiral centres and some have geometricisomeric centres (E- and Z-isomers), and it is understood that theinvention encompasses all such optical, diastereoisomeric and geometricisomers.

In one aspect of the invention there is provided the use of a compoundof formula (I) in therapy.

In a further aspect of the invention there is provided the use of acompound of formula (I) in anticoagulant therapy.

In still a further aspect of the invention there is provided the use ofa compound of formula (I) in the treatment of a condition whereinhibition of thrombin is beneficial.

In still a further aspect of the invention there is provided the use ofa compound of formula (I) in the treatment and prevention ofthromboembolic disorders.

In still a further aspect of the invention there is provided a method oftreatment of a condition where inhibition of thrombin is beneficial,which method comprises administration of a therapeutically effectiveamount of a compound of formula (I) to a person suffering from, orsusceptible to, such a condition.

In still a further aspect of the invention there is provided a method oftreatment and prevention of thromboembolic disorders, which methodcomprises administration of a therapeutically effective amount of acompound of formula (I) to a person suffering from, or susceptible to,thrombophilia conditions.

In a further aspect of the invention there is provided pharmaceuticalformulations comprising a therapeutically effective amount of a compoundof formula (I), in admixture with at least one pharmaceuticallyacceptable diluent, excipients and/or inert carrier.

In yet a further aspect of the invention there is provided apharmaceutical formulation comprising a compound of formula (I) for usein the treatment of those conditions where inhibition of thrombin isbeneficial, such as thrombo-embolism and/or conditions whereanticoagulant therapy is indicated.

In another aspect of the invention there is provided a process for thepreparation of compounds of formula (I), and the intermediates used inthe preparation thereof.

These and other aspects of the present invention are described ingreater detail herein below.

DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is to provide compounds that arecompetitive inhibitors of trypsin-like serine proteases, especiallythrombin, their use as medicaments, pharmaceutical compositionscontaining them and synthetic routes to their production.

Listed below are definitions of various terms used in the specificationand claims to describe the present invention.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by “hereinbefore defined”, “definedhereinbefore” or “defined above” the said group encompasses the firstoccurring and broadest definition as well as each and all of the otherdefinitions for that group.

For the avoidance of doubt it is to be understood that in thisspecification “C₁₋₆” means a carbon group having 1, 2, 3, 4, 5 or 6carbon atoms and “C₁₋₄” means a carbon group having 1, 2, 3 or 4 carbonatoms.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl groups and may be, butare not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl,i-hexyl or t-hexyl.

In this specification, unless stated otherwise, the term “cycloalkyl”refers to a saturated cyclic hydrocarbon ring system. The term “C₃₋₆cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In this specification, unless stated otherwise, the term “alkenyl”includes both straight and branched chain alkenyl groups. The term C₂₋₆alkenyl includes alkenyl groups having 2 to 6 carbon atoms and one ortwo double bonds, and may be, but is not limited to, vinyl, allyl,propenyl, butenyl, crotyl, pentenyl, or hexenyl, and a butenyl group mayfor example be buten-2-yl, buten-3-yl or buten-4-yl.

In this specification, unless stated otherwise, the term “alkynyl”includes both straight and branched chain alkynyl groups. The term C₂₋₆alkynyl includes alkynyl groups having 2 to 6 carbon atoms and one ortwo triple bonds, and may be, but is not limited to, etynyl, propargyl,pentynyl or hexynyl and a butynyl group may for example be butyn-3-yl orbutyn-4-yl.

In this specification, unless stated otherwise, the term “cycloalkenyl”refers to a non-aromatic cyclic hydrocarbon ring system containing oneor two double bonds. The term “C₄₋₇ cycloalkenyl” may be, but is notlimited to, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyland a cyclopentenyl group may for example be cyclopenten-3-yl orcyclopenten-4-yl.

In this specification, unless stated otherwise, the term “alkoxy”includes both straight or branched alkoxy groups. C₁₋₆ alkoxy may be,but is not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, s-butoxy, t-butoxy, n-pentoxy, i-pentoxy, t-pentoxy,neo-pentoxy, n-hexyloxy, i-hexyloxy or t-hexyloxy.

In this specification, unless stated otherwise, the term “5-memberedheteroaryl ring containing 2, 3 or 4 heteroatoms, selected from N, O andS, wherein at least 2 heteroatoms are N, and 0 or 1 heteroatoms are O orS” includes aromatic heterocyclic rings. Examples of such rings areimidazole, tetrazole, triazole, thiadiazole or oxadiazole.

In this specification, unless stated otherwise, the term “6-memberedheteroaryl ring containing 1 or 2 nitrogen atoms” includes pyridine,pyridazine, pyrimidine or pyrazine.

In this specification, unless stated otherwise, the term “4-, 5- or6-membered cycloheteroalkyl ring having 1 or 2 heteroatoms selected fromO, S and N” includes oxetane, azetidine, oxazetidine, pyrrolidine,imidazoline, tetrahydrofuran, oxazolidine, piperidine, piperazine,hexahydropyridazine, hexahydropyrimidine, morpholine, oxazinane,thietane, thietane 1-oxide, thietane 1,1-dioxide, tetrahydra-thiophene,tetrahydra-thiophene 1-oxide, tetrahydra-thiophene 1,1-dioxide,tetrahydra-thiopyran, tetrahydra-thiopyran 1-oxide ortetrahydra-thiopyran 1,1-dioxide.

In this specification, unless stated otherwise, the term “5 or6-membered heteroaromatic ring containing 1, 2 or 3 heteroatomsindependently selected from O, S and N” includes furan, thiophene,pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole,thiadiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine ortriazine.

In this specification, unless stated otherwise, the term “phenyl-fused5- or 6-membered cycloheteroalkyl ring containing 1 or 2 heteroatomsindependently selected from O, S and N” includes indoline,dihydroisoindole, dihydrobenzofuran, dihydroisobenzofuran,dihydrobenzothiophene, dihydrobenzoimidazole, dihydroindazole,dihydrobenzooxazole, dihydrobenzothiazole, tetrahydroquinoline,tetrahydroisoquinoline, tetrahydroquinoxaline, tetrahydraquinazoline,tetrahydrophtalazine, chroman, isochroman, thiochroman, isothiochroman,dihydrobenzooxazine or dihydrobenzothiazine.

In this specification, unless stated otherwise, the term “halogen” maybe fluoro, chloro, bromo or iodo.

In this specification,

represents motifs of the following structures

In one embodiment of the invention R¹ is a 5-membered heteroaryl ringcontaining 2, 3 or 4 heteroatoms, selected from N, O and S, wherein atleast 2 heteroatoms are N, and 0 or 1 heteroatoms are O or S, whereinsaid 5-membered heteroaryl ring is substituted, at any carbon ring atom,by 0, 1 or 2 substituents independently selected from C₁₋₆ alkyl and a6-membered heteroaryl ring containing 1 or 2 nitrogen atoms, whereinsaid 6-membered heteroaryl ring is substituted, at any carbon ring atom,by 0, 1, 2 or 3 substituents independently selected from C₁₋₆ alkyl.

In a further embodiment of the invention R¹ is a 5-membered heteroarylring containing 2, 3 or 4 heteroatoms, selected from N, O and S, whereinat least 2 heteroatoms are N, and 0 or 1 heteroatom is O or S.

In a further embodiment of the invention R¹ is tetrazole.

In one embodiment of the invention R² is H, halogen, cyano, C₁₋₆ alkylor C₁₋₆ alkoxy, wherein said C₁₋₆ alkyl or C₁₋₆ alkoxy is substituted by0, 1, 2, 3, 4 or 5 halogen.

In a further embodiment of the invention R² is H or halogen.

In still another embodiment of the invention R² is H, Cl or F.

In one embodiment of the invention the stereochemical configurationaround the carbon in the pyrazolidine, dihydropyrazole or isoxazolidine,i.e. the ring containing X and Y, which is covalently bound to thecarbonyl is (S).

In one embodiment of the invention G is

In a further embodiment of the invention G is

R³ is H, R⁵, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₃₋₆ cycloalkyl,wherein each of said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆cycloalkyl are independently substituted by 0, 1, 2, 3, 4 or 5substituents selected from halogen and 0, 1 or 2 substituents selectedfrom OH, oxo, cyano, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₄₋₇ cycloalkenyl, cycloheteroalkyl, R⁵ and R⁶,

-   -   wherein R⁵ is phenyl, a 5 or 6-membered heteroaromatic ring        containing 1, 2 or 3 heteroatoms independently selected from O,        S and N, a 4-, 5- or 6-membered cycloheteroalkyl ring containing        1 or 2 heteroatoms independently selected from O, S and N or a        phenyl-fused 5- or 6-membered cycloheteroalkyl ring containing 1        or 2 heteroatoms independently selected from O, S and N, wherein        said phenyl, said heteroaromatic ring, said cycloheteroalkyl        ring and said phenyl-fused cycloheteroalkyl ring are        substituted, at any carbon ring atom, by 0, 1, 2, 3, 4 or 5        substituents independently selected from COOH, OH, halogen, CF₃,        CHF₂, CH₂F, cyano, C₁₋₆ alkyl, R⁶ and SO₂R⁷;    -   R⁶ is C₁₋₆ alkoxy, wherein said C₁₋₆ alkoxy is substituted by 0,        1, 2, 3, 4 or 5 halogen; and    -   R⁷ is C₁₋₆ alkyl;

R⁴ is OH, OC(O)R⁷, OC(O)R⁸ or NHR⁹;

R⁸ is phenyl, wherein said phenyl is substituted by 0, 1, 2, 3, 4 or 5substituents independently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,F, CF₃, CHF₂ and CH₂F or

C₁₋₄ alkyl, wherein said C₁₋₄ alkyl is substituted by 0, 1, 2 or 3substituents independently selected from methyl and ethyl and 0 or 1substituents selected from phenyl, wherein said phenyl is substituted by0, 1, 2, 3, 4 or 5 substituents independently selected from C₁₋₄ alkyl,C₁₋₄ alkoxy, cyano, F, CF₃, CHF₂, CH₂F and OCOR⁷;

R⁹ is H, COOR⁷ or SO₂R⁷ wherein said R⁷ is substituted by 0, 1, 2 or 3substituents independently selected from OH, halogen, cyano, R⁶ and C₃₋₇cycloalkyl;

-   -   wherein R⁶ is C₁₋₆ alkoxy, wherein said C₁₋₆ alkoxy is        substituted by 0, 1, 2, 3, 4 or 5 halogen; and    -   R⁷ is C₁₋₆ alkyl.

In a further embodiment of the invention G is

R³ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, a 5 or 6-membered heteroaromatic ringcontaining 1, 2 or 3 heteroatoms independently selected from O, S and N,

a 4-, 5- or 6-membered cycloheteroalkyl ring containing 1 or 2heteroatoms independently selected from O, S and N, or R¹², wherein saidC₁₋₆ alkyl, said C₃₋₆ cycloalkyl, said heteroaromatic ring and saidcycloheteroalkyl ring are substituted by 0 or 1 substituents selectedfrom NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₃ cycloalkyl, R⁶ or R¹²,

-   -   wherein R⁶ is C₁₋₆ alkoxy, wherein said C₁₋₆ alkoxy is        substituted by 0, 1, 2, 3, 4 or 5 halogen;    -   R¹² is phenyl, wherein said phenyl is substituted by 0, 1 or 2        substituents selected from halogen and R⁶; and

R⁴ is OH, OC(O)R⁷, OC(O)R⁸ or NH₂,

-   -   wherein R⁷ is C₁₋₆ alkyl;    -   R⁸ is phenyl, wherein said phenyl is substituted by 0, 1, 2, 3,        4 or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄        alkoxy, cyano, F, CF₃, CHF₂ and CH₂F or    -   C₁₋₄ alkyl, wherein said C₁₋₄ alkyl is substituted by 0, 1, 2 or        3 substituents independently selected from methyl and ethyl and        0 or 1 substituents selected from phenyl, wherein said phenyl is        substituted by 0, 1, 2, 3, 4 or 5 substituents independently        selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, F, CF₃, CHF₂, CH₂F        and OCOR⁷.

In a still further embodiment of the invention G is

R³ is C₃₋₆ cycloalkyl, R¹² or C₁₋₆ alkyl, wherein said C₁₋₆ alkyl issubstituted by 0 or 1 substituents selected from C₃ cycloalkyl, N(C₁₋₄alkyl)₂, R⁶ or R¹²,

-   -   wherein R⁶ is C₁₋₆ alkoxy, wherein said C₁₋₆ alkoxy is        substituted by 0, 1, 2, 3, 4 or 5 halogen; and    -   R¹² is phenyl, wherein said phenyl is substituted by 0, 1 or 2        substituents selected from halogen; and

R⁴ is OH or OC(O)R⁷.

In one embodiment of the invention the stereochemical configurationaround the carbon substituted by R³ and R⁴ in G is (R).

In a further embodiment G is

R¹⁰ is 0, 1, 2, 3, 4 or 5 substituents selected from halogen, OH, oxo,cyano, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, R⁵ and R⁶, wherein said C₁₋₄ alkylis substituted by 0 or 1 substituent selected from R⁵, NH₂, NH(C₁₋₄alkyl) or N(C₁₋₄ alkyl)₂;

R⁵ is phenyl, which is substituted, by 0, 1, 2, 3, 4 or 5 substituentsindependently selected from COOH, OH, halogen, CF₃, cyano, C₁₋₆ alkyl,R⁶ and SO₂R⁷,

-   -   wherein R⁶ is C₁₋₆ alkoxy, wherein said C₁₋₆ alkoxy is        substituted by 0, 1, 2, 3, 4 or 5 halogen; and    -   R⁷ is C₁₋₆ alkyl;

Q is O, CH₂ or S(O)_(n);

n is independently 0, 1 or 2; and

each t is independently 0, 1 or 2.

In a still further embodiment of the invention G is

Q is O or CH₂;

each t is independently 0 or 1;

R¹⁰ is 0, 1 or 2 substituents selected from oxo, C₁₋₄ alkyl, R⁵ and R⁶;and

R⁵ is phenyl, which is substituted by 0, 1, 2, 3, 4 or 5 substituentsindependently selected from COOH, OH, halogen, CF₃, cyano, C₁₋₆ alkyl,R⁶ and SO₂R⁷;

-   -   wherein R⁶ is C₁₋₆ alkoxy, wherein said C₁₋₆ alkoxy is        substituted by 0, 1, 2, 3, 4 or 5 halogen; and    -   R⁷ is C₁₋₆ alkyl;

In a still further embodiment of the invention G is

Q is O or CH₂; and

each t is independently 0 or 1; and

R¹⁰ is 0, 1 or 2 substituents selected from oxo and C₁₋₄ alkyl.

In a further embodiment of the invention G is

R⁴ is OH, OC(O)R⁷, OC(O)R⁸ or NHR⁹;

-   -   wherein R⁷ is C₁₋₆ alkyl;    -   R⁸ is phenyl, wherein said phenyl is substituted by 0, 1, 2, 3,        4 or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄        alkoxy, cyano, F, CF₃, CHF₂ and CH₂F or    -   C₁₋₄ alkyl, wherein said C₁₋₄ alkyl is substituted by 0, 1, 2 or        3 substituents independently selected from methyl and ethyl and        0 or 1 substituents selected from phenyl, wherein said phenyl is        substituted by 0, 1, 2, 3, 4 or 5 substituents independently        selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, F, CF₃, CHF₂, CH₂F        and CO₂R⁷; and    -   R⁹ is H, COOR⁷ or SO₂R⁷ wherein said R⁷ is substituted by 0, 1,        2 or 3 substituents independently selected from OH, halogen,        cyano, R⁶ and C₃₋₇ cycloalkyl;

Q is O, CH₂ or S(O)_(n);

W is C or N;

n is independently 0, 1 or 2;

u is independently 0 or 1; and

R¹⁰ is 0, 1, 2, 3, 4 or 5 substituents selected from halogen, OH, oxo,cyano, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, R⁵ and R⁶, wherein said C₁₋₄ alkylis substituted by 0 or 1 substituent selected from R⁵, NH₂, NH(C₁₋₄alkyl) or N(C₁₋₄ alkyl)₂;

R¹¹ is 0, 1, 2, 3, 4 or 5 substituents selected from halogen, OH, cyano,C₁₋₄ alkyl, C₃₋₆ cycloalkyl, R⁵ and R⁶, wherein said C₁₋₄ alkyl issubstituted by 0 or 1 substituents selected from R⁵, NH₂, NH(C₁₋₄ alkyl)or N(C₁₋₄ alkyl)₂;

-   -   R⁵ is phenyl, which is substituted, by 0, 1, 2, 3, 4 or 5        substituents independently selected from COOH, OH, halogen, CF₃,        cyano, C₁₋₆ alkyl, R⁶ and SO₂R⁷, wherein R⁶ is C₁₋₆ alkoxy,        wherein said C₁₋₆ alkoxy is substituted by 0, 1, 2, 3, 4 or 5        halogen; and    -   R⁷ is C₁₋₆ alkyl.

In a still further embodiment of the invention G is

R⁴ is OH, OC(O)R⁷, OC(O)R⁸ or NH₂,

-   -   wherein R⁷ is C₁₋₆ alkyl;    -   R⁸ is phenyl, wherein said phenyl is substituted by 0, 1, 2, 3,        4 or 5 substituents independently selected from C₁₋₄ alkyl, C₁₋₄        alkoxy, cyano, F, CF₃, CHF₂ and CH₂F or    -   C₁₋₄ alkyl, wherein said C₁₋₄ alkyl is substituted by 0, 1, 2 or        3 substituents independently selected from methyl and ethyl and        0 or 1 substituents selected from phenyl, wherein said phenyl is        substituted by 0, 1, 2, 3, 4 or 5 substituents independently        selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, F, CF₃, CHF₂, CH₂F        and CO₂R⁷;

Q is O or CH₂;

u is independently 0 or 1; and

R¹⁰ is 0, 1 or 2 substituents selected from C₁₋₄ alkyl, halogen and R⁶;

R¹¹ is 0, 1 or 2 substituents selected from C₁₋₄ alkyl, halogen and R⁶,

-   -   wherein R⁶ is C₁₋₆ alkoxy, wherein said C₁₋₆ alkoxy is        substituted by 0, 1, 2, 3, 4 or 5 halogen.

In a still further embodiment of the invention G is

R⁴ is OH or OC(O)R⁷;

R¹⁰ is 0, 1 or 2 substituents selected from C₁₋₄ alkyl, F, Cl, OCH₃,OCF₃, OCHF₂ and OCH₂F;

R¹¹ is 0, 1 or 2 substituents selected from C₁₋₄ alkyl, F, Cl, OCH₃,OCF₃, OCHF₂ and OCH₂F;

Q is O or CH₂; and

u is independently 0 or 1.

In one embodiment of the invention the compound of formula (I) isselected from:

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2,3-difluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)-1-[(2R)-3-tert-Butoxy-2-hydroxypropanoyl]-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(3,5-difluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-cyclopentyl-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2,4-difluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-2-(3-methylphenyl)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-5-methylhexanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2-fluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxyhexanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3-(1-methylcyclopropyl)propanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(4-hydroxy-3,4-dihydro-2H-chromen-4-yl)carbonyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-2-phenylacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-4,4-dimethylpentanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-cyclohexyl-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3-methoxy-3-methylbutanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3-phenylpropanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-(4-methyl-D-leucyl)-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-3-cyclopropyl-2-hydroxypropanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(3-cyanophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2S)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,

[(1R)-2-[(5S)-5-[[5-Chloro-2-(tetrazol-1-yl)phenyl]methylcarbamoyl]-4,5-dihydropyrazol-1-yl]-1-(4-fluorophenyl)-2-oxo-ethyl]acetate,

(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethyl3-methylbutanoate,

(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethylbutanoate,

(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethyl2-methylpropanoate,

(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethylpentanoate,

(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethylpropanoate,

(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethylbenzoate,

(R)-2-((S)-5-(5-Chloro-2-(1H-tetrazol-1-yl)benzylcarbamoyl)-4,5-dihydro-1H-pyrazol-1-yl)-1-(4-fluorophenyl)-2-oxoethyl3-(2,4-dimethyl-6-(propionyloxy)phenyl)-3-methylbutanoate,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]isoxazolidine-3-carboxamide,

(3S)-2-(O-tert-Butyl-D-seryl)-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2,4-difluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2,3-difluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(3,5-difluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2-fluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[hydroxy(3-methylphenyl)acetyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxyhexanoyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-5-methylhexanoyl]isoxazolidine-3-carboxamide,

(3S)-2-[(2R)-3-tert-Butoxy-2-hydroxypropanoyl]-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-cyclopentyl-2-hydroxyacetyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-cyclohexyl-2-hydroxyacetyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3-(1-methylcyclopropyl)propanoyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-2-phenylacetyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-4,4-dimethylpentanoyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3-phenylpropanoyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(3-cyanophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-2-phenylacetyl]pyrazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2-fluorophenyl)(hydroxy)acetyl]pyrazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2,4-difluorophenyl)(hydroxy)acetyl]pyrazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]pyrazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(4-hydroxy-3,4-dihydro-2H-chromen-4-yl)carbonyl]pyrazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-4,4-dimethylpentanoyl]pyrazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-cyclohexyl-2-hydroxyacetyl]pyrazolidine-3-carboxamide,

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3-phenylpropanoyl]pyrazolidine-3-carboxamideor

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]pyrazolidine-3-carboxamide,

or a pharmaceutically acceptable salt or an enantiomer or apharmaceutically acceptable salt of said enantiomer.

In another aspect of the present invention there is provided a compoundof formula (X)

X is N, O or NH;

Y is CH₂ when X is O or NH, with X and Y connected via a single bond, or

Y is CH when X is N, with X and Y connected via a double bond;

R³ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, a 5 or 6-membered heteroaromatic ringcontaining 1, 2 or 3 heteroatoms independently selected from O, S and N,

a 4-, 5- or 6-membered cycloheteroalkyl ring containing 1 or 2heteroatoms independently selected from O, S and N, or R¹², wherein saidC₁₋₆ alkyl, said C₃₋₆ cycloalkyl, said heteroaromatic ring and saidcycloheteroalkyl ring are substituted by 0 or 1 substituents selectedfrom NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₃ cycloalkyl, R⁶ or R¹²;

R⁶ is C₁₋₆ alkoxy, wherein said C₁₋₆ alkoxy is substituted by 0, 1, 2,3, 4 or 5 halogen; and

R¹² is phenyl, wherein said phenyl is substituted by 0, 1 or 2substituents selected from halogen and R⁶.

In yet another aspect of the present invention there is provided acompound of formula (XI)

X is N, O or NH;

Y is CH₂ when X is O or NH, with X and Y connected via a single bond, or

Y is CH when X is N, with X and Y connected via a double bond;

Q is O or CH₂;

u is independently 0 or 1; and

R¹⁰ is 0, 1 or 2 substituents selected from C₁₋₄ alkyl, halogen and R⁶;

R¹¹ is 0, 1 or 2 substituents selected from C₁₋₄ alkyl, halogen and R⁶;

R⁶ is C₁₋₆ alkoxy, wherein said C₁₋₆ alkoxy is substituted by 0, 1, 2,3, 4 or 5 halogen.

The present invention further provides a process for the preparation ofa compound of formula (I) as defined above which comprises:

(A) reacting a compound of formula (II),

wherein X and Y are as defined in formula (I), or a derivative thereofthat is protected at the amino group, with an amine of formula (III)

wherein R¹ and R² are as defined in formula (I) to deliver a compound offormula (IV), or a derivative thereof that is protected at the aminogroup,

(B) reacting a compound of formula (IV),

wherein X, Y, R¹ and R² are as defined in formula (I), with a compoundof formula (V)

wherein R³ is as hereinbefore defined and R⁴ is OH, or a derivativethereof that is either protected at the hydroxy substituent or at boththe hydroxy substituent and at the carboxylic acid, to deliver acompound of formula (I);

(C) reacting a compound of formula (IV),

wherein X, Y, R¹ and R² are as defined in formula (I), with a compoundof formula (VI)

wherein R¹⁰, R¹¹, W, Q and u are as hereinbefore defined and R⁴ is OH,or a derivative thereof that is either protected at the hydroxysubstituent or at both the hydroxy substituent and at the carboxylicacid, to deliver a compound of formula (I);

(D) reacting a compound of formula (IV),

wherein X, Y, R¹ and R² are as defined in formula (I), with a compoundof formula (V)

wherein R³ is as hereinbefore defined and R⁴ is NHR⁹, wherein R⁹ is ashereinbefore defined, or a derivative thereof that is protected at theamino substituent, to deliver a compound of formula (I);

(E) reacting a compound of formula (IV),

wherein X, Y, R¹ and R² are as defined in formula (I), with a compoundof formula (VI)

wherein R¹⁰, R¹¹, W, Q and u are as hereinbefore defined and R⁴ is NHR⁹,wherein R⁹ is as hereinbefore defined, or a derivative thereof that isprotected at the amino substituent, to deliver a compound of formula(I);

(F) reacting a compound of formula (IV),

wherein X, Y, R¹ and R² are as defined in formula (I), with a compoundof formula (VII)

wherein R¹⁰, Q and t are as hereinbefore defined, or a derivativethereof that is protected at the amino group, to deliver a compound offormula (I);

(G) reacting a compound of formula (II),

wherein X and Y are as defined in formula (I), or a derivative thereofthat is protected at the carboxylic acid, with a compound of formula (V)

wherein R³ is as hereinbefore defined and R⁴ is OH, or a derivativethereof that is either protected at the hydroxy substituent or at boththe hydroxy substituent and at the carboxylic acid, to deliver acompound of formula (VIII);

(H) reacting a compound of formula (II),

wherein X and Y are as defined in formula (I), or a derivative thereofthat is protected at the carboxylic acid, with a compound of formula(VI)

wherein R¹⁰, R¹¹, W, Q and u are as hereinbefore defined and R⁴ is OH,or a derivative thereof that is either protected at the hydroxysubstituent or at both the hydroxy substituent and at the carboxylicacid, to deliver a compound of formula (IX)

(I) reacting a compound of formula (VIII), or a derivative thereof thatis protected at the carboxylic acid,

wherein X, Y and R³ is as hereinbefore defined and R⁴ is OH, or aderivative thereof that is protected at the OH group, to deliver acompound of formula (X)

(J) reacting a compound of formula (IX), or a derivative thereof that isprotected at the carboxylic acid,

wherein R¹⁰, R¹¹, X, Y, W, Q and u are as hereinbefore defined and R⁴ isOH, or a derivative thereof that is protected at the OH group, todeliver a compound of formula (XI)

(K) reacting a compound of formula (X) or formula (XI), wherein R³, R¹⁰,R¹¹, X, Y, W, Q and u are as hereinbefore defined with a compound offormula (III), wherein R¹ and R² are as hereinbefore defined, to delivera compound of formula (I);

(L) reacting a compound of formula (II),

wherein X and Y are as defined in formula (I), or a derivative thereofthat is protected at the carboxylic acid, with a compound of formula(XII)

wherein R³ is as hereinbefore defined, to deliver a compound of formula(XIII)

(M) reacting a compound of formula (XIII), wherein X, Y and R³ are ashereinbefore defined, or a derivative thereof that is protected at thecarboxylic acid, under reducing conditions to deliver a compound offormula (VIII)

(N) reacting a compound of formula (XIV),

wherein R¹²is OH, alkoxy, aryloxy or R¹³, wherein R¹³ is a chiralauxiliary, e.g., 2,10-camphorsultam,6,6-dimethyl-7,10-methylen-3-oxa-1-azaspiro[4.5]decan-2-one or4-benzyl-2-oxazolidinone, with trimethylsilyldiazomethane to deliver acompound of formula (XV)

wherein Y is CH, X is N, R¹² is OH, alkoxy, aryloxy or R¹³ and the bondbetween X and Y is a double bond.

(O) reacting a compound of formula (XVI),

wherein R¹² is OH or alkoxy, L is Cl, Br, I or OSO₂CF₃ and X is O, N ora protected derivative thereof, in the presence of base to deliver acompound of formula (XV)

wherein Y is CH₂, X is N or O, R¹² is OH or alkoxy and the bond betweenX and Y is a single bond.

Processes (A)-(H) and (L) may be carried out using known procedures forpreparation of amides from carboxylic acids, or analogously, e.g. ashereinafter described in the Examples. It may be carried out in asolvent, e.g. DCM, MeCN, H₂O, EtOAc or DMF, in the presence of anappropriate base, e.g. pyridine, DMAP, NMM, TEA, NaHCO₃, 2,4,6-collidineor DIPEA, and a suitable reagent, e.g. oxalyl chloride, cyanuricfluoride, EDC/HOBt, DCC/HOBt, HBTU, HATU, PyBOP, T3P or TBTU. Thereaction temperature may be from 0° C. to 100° C., or at the refluxtemperature of the solvent if <100° C., but conveniently roomtemperature.

Processes (I) and (J) may be carried out using known procedures forpreparation of lactones, or analogously, e.g. as hereinafter describedin the Examples. It may be carried out in an organic solvent, e.g.CHCl₃, benzene, toluene, EtOH or THF, in the presence of a suitablereagent, e.g. TsOH, MsOH, NaOH, pivaloyl chloride/TEA or DMAP/BOP. Thereaction temperature may be from 0° C. to 100° C., or at the refluxtemperature of the solvent if <100° C., but conveniently roomtemperature.

Process (K) may be carried out using known procedures for preparation ofamides from lactones, or analogously, e.g. as hereinafter described inthe Examples. It may be carried out in an organic solvent, e.g. DCM, THFor MeOH, in the presence of a suitable reagent, e.g. TEA. The reactiontemperature may be from 0° C. to 100° C., or at the reflux temperatureof the solvent if <100° C., but conveniently room temperature.

Process (M) may be carried out using known procedures for preparation ofalcohols from ketones, or analogously, e.g. as hereinafter described inthe Examples. It may be carried out in an organic solvent, e.g. THF, inthe presence of a suitable reagent, e.g. NaBH₄, Zn(BH₄)₂, Ph₂SiH₂ in thepresence of a suitable catalyst, e.g. Rh(PPh₃)₃Cl orRh(I)-2-(2-pyridyl)-4-carbomethoxy-1,3-thiazolidine, or, alternatively,in the presence of H₂ and a suitable catalyst, e.g. Ru/C, Rh-DIOP orRh-CYDIOP. The reaction temperature may be from 0° C. to 100° C., or atthe reflux temperature of the solvent if <100° C., but conveniently roomtemperature.

Process (N) may be carried out using known procedures for preparation ofpyrazolines from olefins, or analogously, e.g. as hereinafter describedin the Examples. It may be carried out in an organic solvent, e.g.methylene chloride, hexane or THF. The reaction temperature may be from−100° C. to 100° C., or at the reflux temperature of the solvent if<100° C., but conveniently room temperature.

Process (O) may be carried out using known procedures for preparation ofpyrazolidines or isoxazolidines, or analogously, e.g. as hereinafterdescribed in the Examples. It may be carried out in an organic solvent,e.g. THF, in the presence of a suitable reagent, e.g. NaHMDS, LiHMDS ortetrabutylammoniumfluoride. The reaction temperature may be from 0° C.to 100° C., or at the reflux temperature of the solvent if <100° C., butconveniently room temperature.

Processes used for hydrolyzing carboxylic esters to carboxylic acids maybe carried out using known procedures, or analogously, e.g. ashereinafter described in the Examples. It may be carried out in asolvent, e.g. MeCN or H2Od 2O in the presence of an appropriate base,e.g. TEA or DIPEA, or a suitably acid, e.g. HCl, and optionally asuitable reagent, e.g. LiBr. The reaction temperature may be from 0° C.to 100° C., or at the reflux temperature of the solvent if <100° C., butconveniently room temperature.

Compounds of formula (II) and formula (XV) are either commerciallyavailable or may be prepared by known methods (e.g. Tetrahedron Letters1997, 38, 4935-4938 (N—NH—CH₂); J. Am. Chem. Soc. 1997, 119, 8379-8380(N—N═CH); Helv. Chim. Acta 1983, 66, 1241(N—O—C)).

Compounds of formula (III) are either commercially available or may beprepared by known methods (e.g. J. Med. Chem. 2004, 47, 2995).

Compounds of formula (V), (VI), (VII), (XII) and (XIV) are eithercommercially available or may be prepared by known methods.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Synthesis’, 2^(nd) Ed, T. W. Greene and P.G. M. Wuts, Wiley-Interscience (1991) and ‘Protecting Groups’, P. J.Kocienski, Georg Thieme Verlag (1994).

A further embodiment of the invention encompasses pharmaceuticallyacceptable salts of the compounds of formula (I). Where the compound issufficiently acidic, pharmaceutically-acceptable salts include, but arenot limited to, an alkali metal salt for example sodium or potassium, analkaline earth metal salt for example calcium or magnesium, an organicamine salt for example triethylamine, morpholine, N-methylpiperidine,N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine oramino acids for example lysine. Where the compound is sufficientlybasic, pharmaceutically acceptable salts include, but are not limitedto, acid addition salts such as a hydrochloride, hydrobromide,phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate,methanesulfonate or p-toluenesulfonate salt.

There may be more than one cation or anion depending on the number ofcharged functions and the valency of the cations or anions.

For a review on suitable salts, see Berge et al., J. Pharm. Sci., 66,1-19 (1977).

The compounds of formula (I) may be administered in the form of aprodrug which is broken down in the human or animal body to give acompound of the formula (I). Certain compounds of formula (I) maythemselves act as prodrugs of other compounds of formula (I). Prodrugsof formula (I) may display improved physicochemical, biopharmaceuticalor pharmacokinetic properties. Examples of prodrugs include in vivohydrolysable esters of a compound of the formula (I).

An in vivo hydrolysable (or cleavable) ester of a compound of theformula (I) that contains a carboxy or a hydroxy group is, for example,a pharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. For examples of esterprodrugs derivatives, see: Curr. Drug. Metab. 2003, 4, 461.

Various other forms of prodrugs are known in the art. For examples ofprodrug derivatives, see: Rautio, J. et al. Nature Reviews DrugDiscovery 2008, 7, 255 and references cited therein.

Medical and Pharmaceutical Use

The compounds of the invention are thus expected to be useful in thoseconditions where inhibition of thrombin is beneficial (as determined byreference to a clinically relevant end-point, e.g. conditions, such asthrombo-embolisms, where inhibition of thrombin is required or desired,and/or conditions where anticoagulant therapy is indicated), includingthe following:

The treatment and/or prophylaxis of thrombosis and hypercoagulability inblood and/or tissues of animals including man. It is known thathypercoagulability may lead to thrombo-embolic diseases. Conditionsassociated with hypercoagulability and thrombo-embolic diseases areusually designated as thrombophilia conditions. These conditionsinclude, but are not limited to, inherited or acquired activated proteinC resistance, such as the factor V-mutation (factor V Leiden), inheritedor acquired deficiencies in antithrombin III, protein C, protein S,protein Z, heparin cofactor II, and conditions with increased plasmalevels of the coagulation factors such as caused by the prothrombinG20210A mutation. Other conditions known to be associated withhypercoagulability and thrombo-embolic disease include circulatingantiphospholipid antibodies (Lupus anticoagulant), homocysteinemi,heparin induced thrombocytopenia and defects in fibrinolysis, as well ascoagulation syndromes (e.g. disseminated intravascular coagulation(DIC)) and vascular injury in general (e.g. due to trauma or surgery).Furthermore, low physical activity, low cardiac output or high age areknown to increase the risk of thrombosis and hypercoagulability may bejust one of several factors underlying the increased risk. Theseconditions include, but are not limited to, prolonged bed rest,prolonged air travelling, hospitalisation for an acute medical disordersuch as cardiac insufficiency or respiratory insufficiency. Furtherconditions with increased risk of thrombosis with hypercoagulability asone component are pregnancy and hormone treatment (e.g. oestrogen).

The treatment of conditions where there is an undesirable excess ofthrombin without signs of hypercoagulability, for example inneurodegenerative diseases such as Alzheimer's disease, in theprogression and/or prevention of atherosclerosis and in growth andspreading of cancer.

Particular disease states which may be mentioned include the therapeuticand/or prophylactic treatment of venous thrombosis (e.g. deep venousthrombosis, DVT) and pulmonary embolism, arterial thrombosis (e.g. inmyocardial infarction, unstable angina and acute coronary syndrome,thrombosis-based stroke and peripheral arterial thrombosis), andsystemic embolism (which may lead to stroke) usually from the atriumduring atrial fibrillation (e.g. non-valvular or valvular atrialfibrillation) or from the left ventricle after transmural myocardialinfarction, or caused by congestive heart failure; prophylaxis ofre-occlusion (i.e. thrombosis) after thrombolysis, percutaneoustrans-luminal interventions (PTI) and coronary bypass operations; theprevention of thrombosis after microsurgery and vascular surgery ingeneral, organ transplantation and plastic surgery.

Further indications include the therapeutic and/or prophylactictreatment of disseminated intravascular coagulation caused by bacteria,multiple trauma, intoxication or any other mechanism; anticoagulanttreatment when blood is in contact with foreign surfaces in the bodysuch as vascular grafts, vascular stents, vascular catheters, mechanicaland biological prosthetic valves or any other medical device; andanticoagulant treatment when blood is in contact with medical devicesoutside the body such as during cardiovascular surgery using aheart-lung machine or in haemodialysis; the therapeutic and/orprophylactic treatment of idiopathic and adult respiratory distresssyndrome, pulmonary fibrosis following treatment with radiation orchemotherapy, chronic obstructive pulmonary disease, septic shock,septicaemia, inflammatory responses, which include, but are not limitedto, edema, acute or chronic atherosclerosis such as coronary arterialdisease and the formation of atherosclerotic plaques, cardiacinsufficiency, cerebral arterial disease, cerebral infarction, cerebralthrombosis, cerebral embolism, peripheral arterial disease, ischemia,angina (including unstable angina), reperfusion damage, restenosis afterpercutaneous trans-luminal interventions (PTI) and coronary arterybypass surgery.

Compounds of the invention that inhibit trypsin and/or thrombin may alsobe useful in the treatment of pancreatitis.

The compounds of the invention are thus indicated both in thetherapeutic and/or prophylactic treatment of these conditions.

According to one aspect of the invention there is thus provided the useof a compound of formula (I) in therapy.

According to a further aspect of the invention there is thus providedthe use of a compound of formula (I) in anticoagulant therapy.

According to still a further aspect of the invention there is thusprovided the use of a compound of formula (I) in the treatment of acondition where inhibition of thrombin is beneficial.

According to still a further aspect of the invention there is thusprovided the use of a compound of formula (I) in the treatment andprevention of thromboembolic disorders.

According to still a further aspect of the invention there is thusprovided the use of a compound of formula (I) for the manufacture of amedicament for the treatment of a condition where inhibition of thrombinis beneficial.

According to still a further aspect of the invention there is thusprovided the use of a compound of formula (I) for the manufacture of amedicament for the treatment and prevention of thromboembolic disorders.

According to still a further aspect of the invention there is thusprovided a method of treatment of a condition where inhibition ofthrombin is beneficial, which method comprises administration of atherapeutically effective amount of a compound of formula (I) to aperson suffering from, or susceptible to, such a condition.

According to still a further aspect of the invention there is thusprovided a method of treatment and prevention of thromboembolicdisorders, which method comprises administration of a therapeuticallyeffective amount of a compound of formula (I) to a person sufferingfrom, or susceptible to, thrombophilia conditions.

The compounds of the invention have the advantage that they may be moreefficacious, be less toxic, be more selective (e.g. for inhibitingthrombin over other serine proteases, in particular trypsin and thoseinvolved in haemostasis), be more potent, produce fewer side effects, bemore easily absorbed, and/or have a better pharmacokinetic profile (e.g.higher oral bioavailability and/or lower clearance), than compoundsknown in the prior art.

Pharmaceutical Formulation

According to a further aspect of the present invention, there isprovided a method of treatment of a condition where inhibition ofthrombin is required which method comprises administration of atherapeutically effective amount of a compound of the invention to aperson suffering from, or susceptible to, such a condition.

The compounds of the invention will normally be administered orally,intravenously, subcutaneously, buccally, rectally, dermally, nasally,tracheally, bronchially, by any other parenteral route or viainhalation, in the form of pharmaceutical preparations comprising acompound of the invention either as a free base, or a pharmaceuticallyacceptable non-toxic organic or inorganic acid addition salt, in apharmaceutically acceptable dosage form.

Preferred route of administration of compounds of the invention is oral.

Depending upon the disorder and patient to be treated and the route ofadministration, the compositions may be administered at varying doses.

The compounds of the invention may also be combined and/orco-administered with any antithrombotic agent(s) with a differentmechanism of action, such as one or more of the following: theanticoagulants unfractionated heparin, low molecular weight heparin,other heparin derivatives, synthetic heparin derivatives (e.g.fondaparinux), vitamin K antagonists, synthetic or biotechnologicalinhibitors of other coagulation factors than thrombin (e.g. syntheticFXa, FVIIa, FIXa and FXIa inhibitors, and rNAPc2), the antiplateletagents acetylsalicylic acid and dipyridamole, thromboxane receptorand/or synthetase inhibitors, fibrinogen receptor antagonists,prostacyclin mimetics, phosphodiesterase inhibitors, ADP-receptor (P2X₁,P2Y₁, P2Y₁₂ [e.g. ticlopidine, clopidogrel, cangrelor, satigrel andAZD6140]) antagonists, inhibitors of phosphoinositide 3-kinase beta orgamma, inhibitors of carboxypeptidase U (CPU or TAFIa) and inhibitors ofplasminogen activator inhibitor-1 (PAI-1, e.g. SCH530348 and E-5555).

The compounds of the invention may further be combined and/orco-administered with thrombolytics such as one or more of tissueplasminogen activator (natural, recombinant or modified), streptokinase,urokinase, prourokinase, anisoylated plasminogen-streptokinase activatorcomplex (APSAC), animal salivary gland plasminogen activators, and thelike, in the treatment of thrombotic diseases, in particular myocardialinfarction.

According to a further aspect of the invention there is thus provided apharmaceutical formulation comprising a compound of formula (I), inadmixture with at least one pharmaceutically acceptable adjuvant,diluent or carrier.

Suitable daily doses of the compounds of the invention in therapeutictreatment of humans are about 0.001-100 mg/kg body weight at peroraladministration and 0.001-50 mg/kg body weight at parenteraladministration.

For the avoidance of doubt, as used herein, the term “treatment”includes therapeutic and/or prophylactic treatment.

EXAMPLES

The invention will now be further explained by reference to thefollowing examples. In the examples, high resolution mass spectra wererecorded on a Micromass LCT mass spectrometer equipped with anelectrospray interface (LC-HRMS). ¹H NMR measurements were performed onVarian UNITY plus 400, 500 and 600 spectrometers, operating at ¹Hfrequencies of 400, 500 and 600 MHz respectively. Chemical shifts aregiven in ppm with the solvent as internal standard. (CH₃)₂SO* of somereported NMR spectra refer to solutions that are taken from aconcentrated sample dissolved in (CH₃)₂SO and diluted with (CD₃)₂SO.Since a substantial amount of (CH₃)₂SO is present in the sample, first apre-scan is run and analysed to automatically suppress the (CH₃)₂SO(2.54 ppm) and H₂O (3.3 ppm) peaks. Thus the intensity of peaks thatreside in these areas around 3.3 ppm and 2.54 ppm are altered. Becauseof this some signals from the compound around these frequencies may havebeen omitted and the omitted area is indicated in the specific Examples.Flash chromatography separations were performed using Merck Silica gel60 (0.063-0.200 mm) The compounds named below were named using ACD/Name9.04 from ACD/Labs.

The following abbreviations are used:

-   DMF Dimethylformamide-   HATU O-(7-Azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium    hexafluorophosphate-   T3P Propylphosphonic anhydride-   TBTU O-Benzotriazolyl tetramethylisouronium tetrafluoroborate-   EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide-   DMAP 4-(Dimethylamino)pyridine-   NMM N-Methylmorpholine-   TEA Triethylamine-   DCM Dichloromethane-   DCC Dicyclohexylcarbodiimide-   BOP Benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   HBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium    hexafluorophosphate-   HOBt 1-Hydroxybenzotriazole-   HOAT 1-Hydroxy-7-azabenzotriazole-   DIPEA N,N-Diisopropylethylamine-   DIOP Phosphine,    [(2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene)]bis[diphenyl-,    trans--   CYDIOP Phosphine,    [(2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene)]bis[dicyclohexyl-,    trans--   NMP 1-N-Methyl-2-pyrrolidinone-   TBME tert-Butyl methyl ether

Example 1

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide(i) (2R)-(4-Fluorophenyl)(hydroxy)acetic acid

The reaction was performed in a 1 L reactor under an atmosphere ofnitrogen with 200 rpm stirring. 2-(4-Fluorophenyl)-2-hydroxyacetic acid(139 g, 816.98 mmol) was charged into the reactor. Ethanol (800 mL) wasadded which resulted in a turbid mixture. The mixture was heated toreflux with a ramp of 1° C./min. (R)-(+)-1-phenylethylamine (68.5 mL,531.04 mmol) was then added within 5 minutes. The clear homogenoussolution was then allowed to slowly cool to 60° C. with a ramp of 1°C./min. When that temperature was reached, seeds of 95:5 diastereomericpurity was added (˜100 mg). Crystallisation now slowly initiated. Thetemperature was ramped down to 20° C. with 0.5° C./min. When thattemperature was reached the mixture was allowed to stir for another 2hours. The mixture was then filtrated. This furnished crystals of theammonium salt (95 g). This salt was then re-crystallised from EtOH(99.5%, 800 mL) using the following procedure: In a 1 L reactor andunder an atmosphere of nitrogen, the salt obtained above was chargedinto the reactor. EtOH (800 mL) was added (a suspension was obtained)and the temperature was then increased to reflux with a ramp of 1°C./min. When all salt was dissolved, the temperature was ramped downwith 1° C./min→65° C. When that temperature was reached (clearhomogenous solution), seeding crystals were added (approximately 0.5 gwas added). Crystallization initiated immediately but very slowly. Thetemperature was then ramped down to 20° C. with 0.5° C./min. The mixturewas then stirred (200 rpm) over night. After filtration and drying invacuo, 67.9 g of the salt was obtained. Chiral HPLC analysis of the freeacid of the salt showed an enantiomeric excess of 95.2% (97.6:2.4 er).The salt was recrystallized one more time from EtOH (99.5%, 500 mL)using the same procedure as described above but the mixture was onlyallowed to stir for 2 hours at room temperature instead of stirring overnight. After filtration and drying, 56.3 g of crystals of the ammoniumsalt were obtained. Chiral HPLC analysis of the free acid showed anenantiomeric excess of 99.1%.

The ammonium salt above was then partitioned between methyl t-butylether (400 mL) and 1M HCl (aq., 300 mL) The aqueous phase was extractedwith TBME (2×100 mL) The pooled organic phase was washed with water (100mL) and then dried (MgSO₄) and concentrated. This furnished the titlecompound as a solid (32.5 g).

(ii) (2R)-(4-Fluorophenyl)[(trimethylsilyl)oxy]acetoyl chloride

To a 0° C. solution of (2R)-(4-fluorophenyl)(hydroxy)acetic acid (20 g,117.55 mmol), DMAP (0.718 g, 5.88 mmol), and pyridine (19.93 mL, 246.86mmol) in dichloromethane (250 mL) was slowly (10 min) addedchlorotrimethylsilane (30.6 mL, 240.98 mmol). The mixture was stirredunder ice-cooling for 15 minutes and then at room temperature overnight. The mixture was then cooled in an ice-bath and DMF (0.211 mL,2.74 mmol) was added followed by the slow (15 min) addition ofoxalylchloride (10.25 mL, 121.08 mmol). The suspension was stirred at 0°C. for 1 hour and for 30 minutes at room temperature. The mixture wasthen used as such in the next step. The yield of(2R)-(4-fluorophenyl)[(trimethylsilyl)oxy]acetoyl chloride is assumed tobe 100%.

(iii) (Alternative 1)Ethyl(5S)-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxylate

Under an atmosphere of nitrogen and on ice-cooling, ethyl acrylate(13.00 mL, 120 mmol) was dissolved in heptane (60 mL) and toluene (60mL). Trimethylsilyldiazomethane (2M in hexanes, 60.0 mL, 120.00 mmol)was added. The solution was then allowed to reach room temperature andwas stirred for 1.5 hour. The mixture was then concentrated underreduced pressure at 30° C. This furnished the crude intermediatecycloadduct which was used without further purification. Under anatmosphere of nitrogen under ice-cooling, to a solution of(2R)-(4-fluorophenyl)[(trimethylsilyl)oxy]acetoyl chloride (30.7 g,117.7, mmol, see (ii) in dichloromethane (250 mL) was slowly (5 minutes)added the crude cycloadduct from above. The mixture was then allowed toreach room temperature and was stirred for 2 hours. LC/MS analysis ofthe crude mixture showed the correct product and one byproduct where thetrimethylsilyl-group still remained intact. Water (300 mL) was added.The aqueous phase was extracted with CH₂Cl₂ (100 mL) The combinedorganic layers were concentrated to give a viscous oil (45 g). To thiswas then added Me-THF (100 mL) and TFA (44.6 mL, 600.00 mmol). Themixture was heated to 78° C. and was stirred over night. Water (200 mL)was added and the mixture was then allowed to stir vigorously for 15minutes. EtOAc (300 mL) was added, the phases separated and the organicphase was concentrated. The crude diastereomeric mixture was thenpurified through silica gel chromatography using an eluent of 20-60%EtOAc in heptane as eluent. Pure fractions containing the desireddiastereomer were collected and concentrated. Recrystallization from hotEtOAc/heptane (30/70, 200 mL) furnished the desired compound as a solid(8.9 g, 25% yield). 1H NMR (600 MHz, CDCl₃) δ 1.29 (t, 3H), 2.91 (ddd,1H), 3.16 (ddd, 1H), 4.12 (d, 1H), 4.21-4.27 (m, 2H), 4.70 (dd, 1H),5.72 (d, 1H), 6.88-6.90 (m, 1H), 6.97-7.01 (2H), 7.39-7.43 (m, 2H).

(iii) (Alternative 2)Ethyl(5S)-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxylate

Under an atmosphere of nitrogen, ethyl acrylate (288 g, 2877 mmol) wasdissolved in dichloromethane (4000 mL) at 20° C. with a stirring rate of150 rpm.

Trimethylsilyldiazomethane (2M in hexanes, 1150 mL, 2301 mmol) was addedover a period of 30 min, after which the mixture was stirred at 20° C.for 19.5 h. After cooling to −30° C., trifluoroacetic acid (443 mL, 5752mmol) was slowly added aver a period of 35 min. A crude mixture of(R)-2-(4-fluorophenyl)-2-(trimethylsilyloxy)acetyl chloride (600 g, 2301mmol) in dichloromethane (4000 ml) was slowly added during 110 min,during which time the temperature was allowed to raise to 20° C. Themixture was stirred at 20° C. for 45 min after which EtOH (500 mL) andwater (500 mL) were added in one portion. The mixture was stirred at 200rpm for 50 min, water (2500 mL) was added, stirred 5 minutes at 200 rpm,then the layers were allowed to separate for 10 minutes. The aqueouslayer (4 L) was separated from the organic one (10.5 L), and to theorganic layer was added a NaHCO3 solution (aq., 8%, 2.5 L). The mixturewas stirred 10 minutes at 200 rpm after which the oganic layer (V=9.75L) was separated from the aqueous one (3000 mL) The crude product in theCH₂Cl₂ solution was concentrated in vacuoo at 40° C. for 15 h. EtOAc(2000 mL) and heptane (1000 mL) were added to the solid and theresulting mixture was heated to reflux. Another 1000 mL of heptane wasadded after which seeding crystals (200 mg) of(5S)—N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamidewas added, resulting in immediate crystallization. The stirring rate wasset at 100 rpm and the temperature was ramped down to 20° C. with 1°C./min and the mixture was then stirred over night. The mixture wasfiltrated through a P3 filter and the filter cake was washed withEtOAc/heptane (50/50, 3×300 ml). The solid was then dried in vacuoo togive the title compound (345 g, 51% yield).

(iv)(5S)-1-[(2R)-2-(4-Fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxylicacid

To a solution of acetonitrile (70 mL), water (1.5 mL) and LiBr (12.69 g,146.12 mmol) was added ethyl(5S)-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxylate(8.6 g, 29.22 mmol) followed by triethylamine (10.13 mL, 73.06 mmol).The homogenous clear solution was then stirred at room temperature overnight. EtOAc (200 mL) and 1M HCl (aq., 150 mL) were added. The aqueousphase was extracted with EtOAc (100 mL) The pooled organic layers werethen concentrated. This furnished 7.2 g of the desired acid as a solid.The pooled aqueous layers was extracted with EtOAc (2×50 mL), followedby washing of the combined organic layers with water (50 mL), anadditional 0.42 g product was isolated. Total yield 98%. 1H NMR [400MHz, (CD₃)₂SO] δ 2.86 (ddd, 1H), 3.23 (ddd, 1H), 4.53 (dd, 1H),5.71-5.77 (m, 2H), 7.07-7.15 (m, 3H), 7.36-7.42 (m, 2H), 12.97 (s, br,1H).

(v)(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

In an open vessel, tert-butyl5-chloro-2-(1H-tetrazol-1-yl)benzylcarbamate (14 g, 45.20 mmol, preparedas described in J. Med. Chem. 2004, 47, 2995, was suspended inacetonitrile (80 mL) HCl (6 M aqueous solution, 37.7 mL, 225.99 mmol)was added and the mixture was then stirred at room temperature for 4hours. Water (200 mL) and TBME (100 mL) were added. To the aqueous phaseand under ice-cooling was added EtOAc (200 mL) followed by slow additionof 2 M NaOH (aq., 130 mL) The organic phase was then washed with water(100 mL) To the EtOAc solution (220 mL) containing the crude(5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanamine was then added(5S)-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxylicacid (7.53 g, 28.28 mmol) followed by the addition of N-methylmorpholine(4.66 mL, 42.43 mmol). To this clear homogenous solution was then addedTBTU (10.90 g, 33.94 mmol) in one portion. The mixture was then stirredat room temperature over night. The precipitate formed was filtrated andthen washed with TBME (100 mL) After drying in vacuo, the desiredcompound was obtained as a solid (7.65 g, 59%). The mother liquor wasdiluted with EtOAc and washed with Na₂CO₃ (aq., sat), water and 1 M HCl(aq.). Crystallization from CH₃CN/water gave 4.59 g of the titlecompound. Total yield 88%. 1H NMR (600 MHz, CD₃CN) δ 2.93 (ddd, 1H),3.10 (ddd, 1H), 4.15-4.19 (m, 2H), 4.25 (dd, 1H), 4.60 (dd, 1H),5.73-5.76 (m, 1H), 6.97-6.99 (m, 1H), 7.07-7.10 (m, 2H), 7.28-7.30 (m,1H), 7.42-7.46 (m, 3H), 7.54-7.56 (m, 1H), 7.71 (d, 1H), 9.20 (s, 1H).

Examples 2-22 were prepared in a manner analogous to Example 1 describedabove using the appropriate starting materials.

Example 2

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2,3-difluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (400 MHz, CD₃OD) for the most potent isomer: δ 9.55 (s, 1H), 7.75(d, 1H), 7.56 (dd, 1H), 7.49 (d, 1H), 7.22-7.13 (m, 2H), 7.13-7.06 (m,1H), 6.95 (br. t, 1H), 6.06 (s, 1H), 4.64 (dd, 1H), 4.30 (d, 1H), 4.24(d, 1H), 3.21-3.08 (m, 1H), 2.90-2.82 (m, 1H), HRMS (ESI) calculated forC₂₀H₁₆ClF₂N₇O₃ 476.1049 (M+H)⁺, found 476.1050.

Example 3

(5S)-1-[(2R)-3-tert-Butoxy-2-hydroxypropanoyl]-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 9.03 (s, 1H), 7.92 (br. t, 1H), 7.59 (d, 1H),7.47 (dd, 1H), 7.28 (d, 1H), 7.06 (s, 1H), 4.90 (d, 1H), 4.89 (dd, 1h),4.33-4.21 (m, 2H), 3.69-3.62 (m, 2H), 3.65-3.58 (m, 1H), 3.07-2.98 (m,1H), 1.13 (s, 9H), HRMS (ESI) calculated for C₁₉H₂₄ClN₇O₄ 450.1660(M+H)⁺, found 450.1680.

Example 4

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(3,5-difluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 8.96 (s, 1H), 7.67 (br. t, 1H), 7.63 (d, 1H),7.48 (dd, 1H), 7.29 (d, 1H), 7.04 (br., 1H), 7.00-6.94 (m, 2H),6.75-6.68 (m, 1H), 5.79 (d, 1H), 4.76 (dd, 1H), 4.29 (d, 2H), 4.15 (d,1H), 3.60-3.52 (m, 1H), 3.03-2.93 (m, 1H), HRMS (ESI) calculated forC₂₀H₁₆ClF₂N₇O₃ 476.1049 (M+H)⁺, found 476.1019.

Example 5

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-cyclopentyl-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (600 MHz, CDCl₃): δ ppm 8.99 (s, 1H), 7.88 (br. s., 1H), 7.59 (d,1H), 7.46 (dd, 1H), 7.30-7.25 (m, 1H), 7.06 (s, 1H), 4.86 (dd, 1H), 4.73(dd, 1H), 4.27 (d, 2H), 3.64 (ddd, 1H), 3.16 (d, 1H), 3.03 (dd, 1H),2.28-2.17 (m, 1H), 1.71-1.60 (m, 3H), 1.56-1.40 (m, 5H).

Example 6

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2,4-difluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CD₃CN) for the most potent isomer: δ 9.23 (s, 1H), 7.73(d, 1H), 7.57 (dd, 1H), 7.48 (d, 1H), 7.40 (q, 1H), 7.33 (bt, 1H),6.93-7.01 (m, 3H), 5.89 (d, 1H), 4.68 (dd, 1H), 4.17-4.31 (m, 3H), 3.12(dd, 1H), 2.95 (dd, 1H). HRMS (ESI) calculated for C₂₀H₁₇ClF₂N₇O₃476.1049 (M+H)⁺, found 476.1042.

Example 7

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-2-(3-methylphenyl)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CDCl₃) for the most potent isomer: δ 9.00 (s, 1H), 7.83(t, 1H), 7.62 (d, 1H), 7.46 (dd, 1H), 7.27-7.16 (m, 4H), 7.11-7.07 (m,1H), 6.95 (s, 1H), 5.77 (s, 1H), 4.74 (dd, 1H), 4.28 (d, 2H), 4.02 (br.,1H), 3.49 (dd, 1H), 2.91 (m, 1H), 2.32 (s, 3H), HRMS (ESI) calculatedfor C₂₁H₂₀ClN₇O₃ 454.1394 (M+H)⁻, found 454.1407.

Example 8

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-5-methylhexanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 9.01 (s, 1H), 7.86 (br. t, 1H), 7.60 (d, 1H),7.47 (dd, 1H), 7.29 (d, 1H), 7.07 (s, 1H), 4.87(dd, 1H), 4.74 (br. t,1H), 4.28 (d, 2H), 3.61 (dd, 1H), 3.20 (d, 1H), 3.06 (dd, 1H), 1.78-1.69(m, 1H), 1.61-1.50 (m, 2H), 1.40-1.29 (m, 2H), 0.89 (t, 6H), HRMS (ESI)calculated for C₁₉H₂₄ClN₇O₃ 434.1707 (M+H)⁺, found 434.1703.

Example 9

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2-fluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CDCl₃) for the most potent isomer: δ 9.00 (s, 1H), 7.81(br. t, 1H), 7.62 (d, 1H), 7.47 (dd, 1H), 7.35 (ddd, 1H), 7.31-7.27 (m,2H), 7.10 (dd, 1H), 7.02 (dd, 1H), 6.91 (br. s, 1H), 5.96 (d, 1H), 4.81(dd, 1H), 4.29(d, 2H), 4.08 (d, 1H), 3.53 (dddd, 1H), 2.98-2.87 (m, 1H),HRMS (ESI) calculated for C₂₀H₁₈ClFN₇O₃ 458.1143 (M+H)⁺, found 458.1136.

Example 10

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxyhexanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (600 MHz, CD₃CN): δ 9.19 (s, 1H), 7.69 (d, 1H), 7.54 (dd, 1H),7.44 (d, 1H), 7.30 (br. t, 1H), 7.04 (br. t, 1H), 4.68-4.63 (m, 2H),4.25-4.13 (m, 2H), 3.29 (d, 1H), 3.20-3.14 (dd, 1H), 2.99-2.94 (dd, 1H),1.76-1.69 (m, 1H), 1.55-1.48 (m, 1H), 1.42-1.28 (m, 4H), 0.91 (t, 3H),HRMS (ESI) calculated for C₁₈H₂₂ClN₇O₃ 420.1551 (M+H)⁺, found 420.1556.

Example 11

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3-(1-methylcyclopropyl)propanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 9.03 (s, 1H), 7.90 (bt, 1H), 7.61 (d, 1H),7.47 (dd, 1H), 7.29 (d, 1H), 7.06 (s, 1H), 4.97 (ddd, 1H), 4.84 (dd,1H), 4.28 (d, 2H), 3.61 (ddd, 1H), 3.17 (d, 1H), 3.04 (ddd, 1H), 1.70(dd, 1H), 1.47 (dd, 1H), 1.16 (s, 3H), 0.20-0.42 (m, 4H). HRMS (ESI)calculated for C₁₉H₂₃ClN₇O₃ 432.1551 (M+H)⁻, found 432.1541.

Example 12

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[4-hydroxy-3,4-dihydro-2H-chromen-4-yl)carbonyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CDCl₃) for the most potent isomer: δ 8.95 (s, 1H), 7.64(bt, 1H), 7.57 (d, 1H), 7.45 (dd, 1H), 7.26 (d, 1H), 7.13 (ddd, 1H),6.82-6.88 (m, 2H), 6.74-6.78 (m, 2H), 4.96 (bs, 1H), 4.86 (dd, 1H),4.18-4.38 (m, 4H), 3.36 (ddd, 1H), 2.78-2.93 (m, 2H), 1.99 (dt, 1H).

Example 13

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-2-phenylacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CD₃OD): δ 9.56 (s, 1H), 7.75 (d, 1H), 7.57 (dd, 1H),7.50 (d, 1H), 7.43-7.47 (m, 2H), 7.23-7.33 (m, 3H), 7.00 (bs, 1H), 5.88(s, 1H), 4.59 (dd, 1H), 4.27 (q, 2H), 3.13 (ddd, 1H), 2.86 (ddd, 1H).HRMS (ESI) calculated for C₂₀H₁₉ClN₇O₃ 440.1238 (M+H)⁺, found 440.1246.

Example 14

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-4,4-dimethylpentanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 9.05 (s, 1H), 7.89 (bt, 1H), 7.61 (d, 1H),7.46 (dd, 1H), 7.28 (d, 1H), 7.05 (s, 1H), 4.89 (ddd, 1H), 4.83 (dd,1H), 4.27 (d, 2H), 3.55 (ddd, 1H), 3.16 (d, 1H), 3.06 (ddd, 1H), 1.53(dd, 1H), 1.40 (dd, 1H), 1.01 (s, 9H). HRMS (ESI) calculated forC₁₉H₂₅ClN₇O₃ 434.1707 (M+H)⁺, found 434.1702.

Example 15

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-cyclohexyl-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 9.08 (s, 1H), 7.92 (bt, 1H), 7.61 (d, 1H),7.44 (dd, 1H), 7.28 (d, 1H), 7.05 (s, 1H), 4.85 (dd, 1H), 4.58 (d, 1H),4.26 (d, 2H), 3.50 (ddd, 1H), 3.09 (ddd, 1H), 2.80 (bs, 1H), 1.43-1.76(m, 6H), 1.06-1.36 (m, 5H). HRMS (ESI) calculated for C₂₀H₂₅ClN₇O₃446.1707 (M+H)⁺, found 446.1739.

Example 16

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3-methoxy-3-methylbutanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (600 MHz, CDCl₃): ca 3:2 mixture of diastereomers, data for majorisomer: δ 9.02 (s, 1H), 7.91 (bt, 1H), 7.53 (d, 1H), 7.40 (dd, 1H), 7.25(d, 1H), 7.01 (s, 1H), 4.75-4.93 (m, 2H), 4.10-4.25 (m, 2H), 3.17 (s,3H), 2.95-3.60 (m, 3H), 1.19 (s, 3H), 1.17 (s, 3H).

Example 17

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3-phenylpropanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CD₃OD): δ 9.54 (s, 1H), 7.73 (s, 1H), 7.55 (d, 1H),7.48 (d, 1H), 7.15-28 (m, 5H), 7.03 (s, 1H), 5.05 (bs, 1H), 4.58-4.65(m, 1H), 4.25 (q, 2H), 3.13-3.23 (m, 1H), 3.01-3.08 (m, 1H), 2.82-2.93(m, 2H). HRMS (ESI) calculated for C₂₁H₂₁ClN₇O₃ 454.1394 (M+H)⁺, found454.1381.

Example 18

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-(4-methyl-D-leucyl)-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CD₃OD): δ 9.54 (s, 1H), 8.90 (bs, 1H), 7.76 (s, 1H),7.58 (d, 1H), 7.51 (d, 1H), 7.23 (s, 1H), 4.75 (bt, 1H), 4.67 (dd, 1H),4.35 (d, 1H), 4.22 (d, 1H), 3.35 (dd, 1H), 2.96 (dd, 1H), 2.02 (dd, 1H),1.66 (dd, 1H), 0.99 (s, 9H). HRMS (ESI) calculated for C₁₉H₂₆ClN₈O₂433.1867 (M+H)⁺, found 433.1877.

Example 19

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-3-cyclopropyl-2-hydroxypropanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CD₃OD): δ 9.55 (s, 1H), 7.74 (s, 1H), 7.56 (d, 1H),7.49 (d, 1H), 7.05 (s, 1H), 4.90 (bs, 1H), 4.65 (dd, 1H), 4.25 (q, 2H),3.23 (dd, 1H), 2.90 (dd, 1H), 1.68-1.75 (m, 1H), 1.40-1.48 (m, 1H),0.85-0.94 (m, 1H), 0.35-0.50 (m, 2H), 0.00-0.10 (m, 2H). HRMS (ESI)calculated for C₁₈H₂₁ClN₇O₃ 418.1394 (M+H)⁻, found 418.1386.

Example 20

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 9.01 (s, 1H), 7.91 (bt, 1H), 7.58 (d, 1H),7.43 (dd, 1H), 7.25 (d, 1H), 7.03 (s, 1H), 4.87 (dd, 1H), 4.63 (s, 1H),4.20-4.30 (m, 2H), 3.56 (dd, 1H), 3.15 (bs, 1H), 2.99 (dd, 1H), 0.93 (s,9H). HRMS (ESI) calculated for C₁₈H₂₃ClN₇O₃ 420.1551 (M+H)⁺, found420.1534.

Example 21

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(3-cyanophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (400 MHz, CD₃CN) for the most potent isomer: δ 9.19 (s, 1H),7.64-7.78 (m, 4H), 7.43-7.57 (m, 3H), 7.27 (bt, 1H), 7.00 (s, 1H), 5.80(d, 1H), 4.60 (dd, 1H), 4.30 (d, 1H), 4.25 (dd, 1H), 4.16 (dd, 1H), 3.10(ddd, 1H), 2.92 (ddd, 1H). HRMS (ESI) calculated for C₂₁H₁₈ClN₈O₃465.1190 (M+H)⁺, found 465.1185.

Example 22

(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2S)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide

¹H NMR (500 MHz, CD₃CN): δ 9.19 (s, 1H), 7.67 (d, 1H), 7.57 (dd, 1H),7.47 (d, 1H), 7.40-7.45 (m, 2H), 7.21 (bt, 1H), 7.01-7.09 (m, 3H), 5.69(d, 1H), 4.74 (dd, 1H), 4.25 (dd, 1H), 4.14 (d, 1H), 4.12 (dd, 1H), 3.19(ddd, 1H), 2.95 (ddd, 1H). HRMS (ESI) calculated for C₂₀H₁₈ClFN₇O₃458.1143 (M+H)⁺, found 458.1135.

Example 23

[(1R)-2-[(5S)-5-[[5-Chloro-2-(tetrazol-1-yl)phenyl]methylcarbamoyl]-4,5-dihydropyrazol-1-yl]-1-(4-fluorophenyl)-2-oxo-ethyl]acetate

To(5S)—N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide(Example 1) (483 mg, 1.05 mmol) in dichloromethane (10 mL) was addedpyridine (2 mL) and acetic anhydride (100 μL, 1.06 mmol). The mixturewas stirred for 4 h. Another portion of acetic anhydride (600 μL, 6.34mmol) and DMAP (23 mg, 0.19 mmol) was added and the mixture was stirredfor is another 15 h. The solvents were removed by evaporation and theresidue was purified by HPLC (MeCN gradient 0 to 100% in aqueous 0.1 MNH₄OAc buffer containing 5% MeCN, C8 column: 50×300 mm) The relevantfractions were collected, combined and freeze dried to give the titlecompound (476 mg, 90%) as a solid material.

¹H NMR (500 MHz, CDCl₃): δ 9.07 (s, 1H), 7.60 (d, 1H), 7.53 (m, 2H),7.46 (dd, 1H), 7.43 (bt, 1H), 7.28 (d, 1H), 7.06 (m, 2H), 7.02 (bt, 1H),6.53 (s, 1H), 4.81 (dd, 1H), 4.27 (dd, 1H), 4.18 (dd, 1H), 3.30 (ddd,1H), 3.11 (ddd, 1H), 2.13 (s, 3H), HRMS (ESI) calculated forC₂₂H₁₉ClFN₇O₄ 500.1249 (M+H)⁺, found 500.1267.

Examples 24-27 were prepared in a manner analogous to Example 23described above using the appropriate starting materials.

Example 24

(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethyl3-methylbutanoate

¹H NMR (500 MHz, (CH₃)₂SO*): δ 9.79 (s, 1H), 8.76 (t, 1H), 7.66 (1H),7.60 (m, 2H), 7.45 (m, 2H), 7.19 (t, 2H), 7.15 (s, 1H), 6.59 (s, 1H),4.54 (dd, 1H), 4.20 (dd, 1H), 4.04 (dd, 1H), 3.13 (dd, 1H), 2.73 (dd,1H), 2.20 (m, 1H), 1.92, (m, 1H), 0.84 (dd, 6H), HRMS (ESI) calculatedfor C₂₅H₂₅ClFN₇O₄ (M+H)⁺, 542.1719 found 542.1715.

Example 25

(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethylbutanoate

¹H NMR (500 MHz, (CH₃)₂SO*): δ 9.80 (s, 1H), 8.49 (t, 1H), 7.67 (1H),7.60 (m, 2H), 7.45 (m, 2H), 7.18 (t, 2H), 7.15 (s, 1H), 6.59 (s, 1H),4.54 (dd, 1H), 4.20 (dd, 1H), 4.05 (dd, 1H), 3.14 (dd, 1H), 2.31 (m,2H), 1.50, (m, 2H), 0.83 (t, 3H), HRMS (ESI) calculated forC₂₄H₂₃ClFN₇O₄ (M+H)⁺, 528.1563 found 528.1573.

Example 26

(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethyl2-methylpropanoate

¹H NMR (500 MHz, (CH₃)₂SO*): δ 9.79 (s, 1H), 8.47 (t, 1H), 7.67 (1H),7.60 (m, 2H), 7.45 (m, 2H), 7.19 (t, 2H), 7.15 (s, 1H), 6.58 (s, 1H),4.54 (dd, 1H), 4.21 (dd, 1H), 4.05 (dd, 1H), 3.15 (dd, 1H), 2.57 (m,1H), 1.07 (d, 3H), 1.03 (d, 3H), HRMS (ESI) calculated for C₂₄H₂₃ClFN₇O₄(M+H)⁺, 528.1563 found 528.1569.

Example 27

(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethylpentanoate

¹H NMR (500 MHz, (CH₃)₂SO*): δ 9.80 (s, 1H), 8.49 (t, 1H), 7.67 (1H),7.60 (m, 2H), 7.45 (m, 2H), 7.19 (t, 2H), 7.15 (s, 1H), 6.58 (s, 1H),4.54 (dd, 1H), 4.20 (dd, 1H), 4.05 (dd, 1H), 3.14 (dd, 1H), 2.73 (dd,1H), 2.33 (m, 2H), 1.45, (m, 2H), 1.24 (m, 2H), 0.80 (t, 3H), HRMS (ESI)calculated for C₂₅H₂₅ClFN₇O₄ (M+H)⁺, 542.1719 found 542.1719.

Example 28

(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethylpropanoate

To a suspension of(5S)—N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide(Example 1) (276 g, 603 mmol) in 2-methyl THF (4.6 L) was added pyridine(62 mL) followed by N,N-dimethylpyridine-4-amine (7.36 g, 723 mmol) andpropionic anhydride (93 mL, 723 mmol). After 2 h the suspension became alittle bit thicker and after 3 h the suspension was very thick. Anotherportion of 2-methyl THF (2 L) was added and an extra impeller wasassembled to the stirring bar. The suspension was stirred at 30° C.(jacket temp) over night. The temperature was then lowered to 15° C. andafter 30 minutes the reaction mixture was filtered through a P3 sinteredglass funnel and the filter cake was washed with ethylacetate (2×250 mL)The white product was dried at 40° C. in vacuo to give the titlecompound (238 g, 77%) as a solid material. To the mother liquor (7.6 L)water (2 L) was added and the phases were separated. The organic phasewas evaporated gently until a thick precipitation was observed. Theslurry was filtered off to get, after drying, a second crop of the titlecompound (37 g, 12%).

¹H NMR (500 MHz, (CDCl₃): δ 9.05 (s, 1H), 7.55 (m, 3H), 7.43 (m, 2H),7.25 (s, 1H), 7.04 (m, 3H), 6.52 (s, 1H), 4.79 (dd, 1H), 4.22 (dd, 2H),3.25 (ddd, 1H), 3.09 (ddd, 1H), 2.41 (m, 2H), 1.03 (t, 3H). HRMS (ESI)calculated for C₂₃H₂₁ClFN₇O₄ (M+H)⁺, 514.1406 found 514.1405.

Example 29

(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethylbenzoate

To a mixture of(3S)—N-[[5-chloro-2-(tetrazol-1-yl)phenyl]methyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxy-acetyl]-3,4-dihydropyrazole-3-carboxamide(0.48 g, 1.05 mmol), pyridine (6 mL, 74 mmol), and DMAP (0.023 g, 0.188mmol) in CH₂Cl₂ (8 mL) at −10° C. was added benzoyl chloride (135 μL,1.15 mmol). The reaction mixture was allowed to attain rt and wasstirred for 5 h. Another portion of benzoyl chloride (400 μL, 3.4 mmol)was added. The mixture was stirred for 60 h. LCMS analysis indicatedonly a trace amount of product. The solvents were removed by evaporationand pyridine (5 mL, 62 mmol) was added followed by another portion ofbenzoyl chloride (400 μL, 3.4 mmol). The reaction mixture was heated to70° C. overnight. LCMS analysis indicated approximately 20% conversionof starting material. The solvent was evaporated of and the residue waspurified by HPLC (MeCN gradient 0 to 100% in 0.1 M NH₄OAc buffercontaining 5% MeCN). The relevant fractions were combined andlyophilized to give the title compound (77 mg, 13%) together with 289 mgof unreacted starting material.

¹H NMR (500 MHz, CDCl₃): δ 9.07 (s, 1H), 7.86 (d, 2H), 7.64 (m, 2H),7.59 (m, 1H), 7.55 (d, 1H), 7.50 (bt, 1H), 7.42 (t, 2H), 7.36 (dd, 1H),7.23 (d, 1H), 7.12-7.05 (m, 3H), 6.77 (s, 1H), 4.81 (dd, 1H), 4.28 (ddd,2H), 3.27 (ddd, 1H), 3.13 (ddd, 1H), HRMS (ESI) calculated forC₂₇H₂₁ClFN₇O₄ 562.1406 (M+H)⁺, found 562.1390.

Example 30

(R)-2-((S)-5-(5-Chloro-2-(1H-tetrazol-1-yl)benzylcarbamoyl)-4,5-dihydro-1H-pyrazol-1-yl)-1-(4-fluorophenyl)-2-oxoethyl3-(2,4-dimethyl-6-(propionyloxy)phenyl)-3-methylbutanoate

To a solution of3-(2,4-dimethyl-6-(propionyloxy)phenyl)-3-methylbutanoic acid (160 mg,0.57 mmol) and(S)—N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-1-((R)-2-(4-fluorophenyl)-2-hydroxyacetyl)-4,5-dihydro-1H-pyrazole-5-carboxamide(263 mg, 0.57 mmol) in DCM (3 mL) and DMF (3 mL) was added EDC (165 mg,0.86 mmol) and DMAP (7 mg, 0.06 mmol). The clear colorless solution wasstirred at rt for 48 h. The mixture was diluted with DCM and washed withwater, 1M HCl and sat NaHCO₃. The organic phase was dried, filtered,evaporated and purified by flash chromatography (DCM/EtOAc gradient from4:1 to 2:1) to give(R)-2-((S)-5-(5-chloro-2-(1H-tetrazol-1-yl)benzylcarbamoyl)-4,5-dihydro-1H-pyrazol-1-yl)-1-(4-fluorophenyl)-2-oxoethyl3-(2,4-dimethyl-6-(propionyloxy)phenyl)-3-methylbutanoate (380 mg, 92%)as a semisolid.

¹H NMR (500 MHz, CDCl₃): δ 9.08 (s, 1H), 7.33-7.48 (m, 5H), 7.22-7.26(m, 1H), 6.95-7.03 (m, 3H), 6.70 (s, 1H), 6.48 (s, 1H), 6.40 (s, 1H),4.77 (dd, 1H), 4.03 (dd, 1H), 3.96 (dd, 1H), 3.21 (ddd, 1H), 2.90-3.10(m, 3H), 2.52 (q, 2H), 2.48 (s, 3H), 2.11 (s, 3H), 1.54 (s, 3H), 1.46(s, 3H), 1.19 (t, 3H). HRMS (ESI) calculated for C₃₆H₃₇ClFN₇O₆ 718.17(M+H)+, found 718.2556 (M+H)+, found 718.2578.

Example 31

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]isoxazolidine-3-carboxamide(i) Ethyl(2S)-4-bromo-2-({[tert-butyl(dimethyl)silyl]oxy}amino)butanoate

To a solution of (R)-4-bromo-2-hydroxy-butyric acid ethyl ester (890 mg,4.217 mmol) in DCM (20 mL) was added trifluoromethanesulfonic anhydride(1.309 g, 4.639 mmol) dropwise at 0° C. After 5 min,2,6-dimethylpyridine (542 mg, 5.060 mmol) was added and the mixture wasallowed to attain rt. After 30 min,O-(tert-butyldimethylsilyl)hydroxylamine (932 mg, 6.326 mmol) and2,6-dimethylpyridine (1.808 g, 16.87 mmol) was added and the reactionmixture was stirred at rt for 48 h. The solvents were evaporated and theresidue was purified by flash chromatography (heptane/EtOAc 20:1, then9:1) to give(S)-4-bromo-2-N-(tert-butyldimethylsilyl)hydroxylamino-butyric acidethyl ester (870 mg, 61%) as an oil.

(ii) Ethyl(3S)-isoxazolidine-3-carboxylate

To a solution ofethyl(2S)-4-bromo-2-({[tert-butyl(dimethyl)silyl]oxy}amino)butanoate(870 mg, 2.556 mmol) in THF (25 mL) was added tetrabutylammoniumfluoridetrihydrate (887 mg, 2.812 mmol) and the mixture was stirred at rt for 1h. The solvents were evaporated and the residue was purified by flashchromatography (DCM/EtOAc 9:1, then 4:1) to giveethyl(3S)-isoxazolidine-3-carboxylate (340 mg, 91%) as an oil.

(iii) 2-tert-Butyl 3-ethyl(3S)-isoxazolidine-2,3-dicarboxylate

To a solution of ethyl (3S)-isoxazolidine-3-carboxylate (1.452 g, 10.00mmol) in DCM (20 mL) was added boc-anhydride (2.62 g, 12.00 mmol),triethylamine (2.02 g, 20.00 mmol) and dimethylaminopyridine (61 mg,0.500 mmol). The reaction mixture was stirred at rt over night and wasthen diluted with TBME and washed with 1 M HCl followed by saturatedNaHCO₃(aq). The organic phase was dried, filtered, evaporated and theresidue was purified by flash chromatography (heptane/EtOAc 4:1, then2:1) to give 2-tert-butyl 3-ethyl(3S)-isoxazolidine-2,3-dicarboxylate(2.20 g, 90%) as an oil.

(iv)tert-Butyl(3S)-3-{[5-chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}isoxazolidine-2-carboxylate

To a solution of 2-tert-butyl3-ethyl(3S)-isoxazolidine-2,3-dicarboxylate (245 mg, 1.00 mmol) inacetonitrile (2.5 mL) and water (1 mL) was added lithium hydroxide (1 Min water, 1.00 mL, 1.00 mmol) and the mixture was stirred at rt for 30min. To this solution was added 5-chloro-2-tetrazol-1-yl-benzylaminehydrochloride (295 mg, 1.20 mmol, prepared as described in J. Med. Chem.2004, 47, 2995), hydroxybenzotriazole (135 mg, 1.00 mmol, as a 20%solution in water, ca 0.65 mL), EDC (288 mg, 1.50 mmol) and NMM (202 mg,2.00 mmol). The resulting mixture was stirred at rt over night, thendiluted with DCM and washed with 1 M HCl and saturated sodium hydrogencarbonate. The organic phase was dried, filtered, evaporated andpurified by flash chromatography (DCM/EtOAc gradient from 4:1 to 1:1) togivetert-butyl(3S)-3-{[5-chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}isoxazolidine-2-carboxylate(357 mg, 87%) as an oil.

(v)(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]isoxazolidine-3-carboxamidehydrochloride

To a solution oftert-butyl(3S)-3-{[5-chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}isoxazolidine-2-carboxylate(357 mg, 0.873 mmol) in MeOH (5 mL) was added conc. HCl (aq., 5 mL) andthe mixture was stirred at rt for 1 h and then evaporated to dryness togive crude(3S)—N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]isoxazolidine-3-carboxamidehydrochloride as a solid which was used as such in the next reactionwithout further purification.

(vi)(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]isoxazolidine-3-carboxamide

To a solution containing dichloromethane (150 mL) and pyridine (11 mL)was added(3S)—N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]isoxazolidine-3-carboxamidehydrochloride (8.40 g, 27.21 mmol) followed by the crude solution of the(R)-2-(4-fluorophenyl)-2-(trimethylsilyloxy)acetyl chloride (7.80 g,29.93 mmol, see Preparation 2) in dichloromethane (˜0.3 M, 100 mL). Theresulting solution was stirred at room temperature for 12 h. MeOH (10mL) was added and the reaction mixture was stirred for another 1 h. Themixture was diluted with dichloromethane (200 mL), washed with 1 M HCl(3×200 mL), sat NaHCO₃ (100 mL) and brine (100 mL), dried, filtered andevaporated to give the crude product. CH₂Cl₂/EtOAc (50 mL, 1:1) wasadded and the mixture was heated to reflux. A solution was obtained.Toluene/EtOAc (1:1, 50 mL) was then added dropwise resulting in someprecipitation. After 12 h the precipitate (6.1 g) was filtered of ¹H NMRanalysis indicated pure product. The mother liquor was evaporated. Tothe residue was added CH₂Cl₂/EtOAc (30 mL, 1:1) and the mixture washeated to reflux. A solution was obtained. Toluene/EtOAc (1:1, 30 mL)was added dropwise. After another 12 h, another 500 mg of precipitatecould be filtered off (this material was pure according to ¹HNMR). Totalyield of(3S)—N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]isoxazolidine-3-carboxamide(6.6 g, 53%).

¹H NMR (600 MHz, CDCl₃) for the most potent isomer: δ 2.25-2.33 (1H),2.58-2.67 (1H), 2.75-2.82 (1H), 3.84-3.89 (1H), 4.11-4.15 (1H),4.24-4.34 (2H), 4.60-4.65 (1H), 5.47-5.51 (1H), 7.01-7.06 (2H),7.26-7.30 (1H), 7.31-7.36 (3H), 7.45-7.48 (1H), 7.60-7.62 (1H), 8.97(1H). HRMS (ES+) calculated for C₂₀H₁₈ClFN₆O₄ 461.1140 (M+H), found461.1122.

Examples 32-48 were prepared in a manner analogous to Example 31described above using the appropriate starting materials.

Example 32

(3S)-2-(O-tert-Butyl-D-seryl)-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]isoxazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 8.99 (s, 1H), 8.00 (br. s, 1H), 7.64 (d, 1H),7.44 (dd, 1H), 7.26 (m, 1H), 6.99 (br. t, 1H), 5.41 (br. s, 1H), 4.44(m, 1H), 4.27-4.02 (m, 4H), 3.89 (dd, 1H), 3.63 (dd, 1H), 3.43 (dd, 1H),2.70 (m, 1H), 2.50 (m, 1H), 1.17 (s, 9H), HRMS (ESI) calculated forC₁₉H₂₇ClN₇O₄ 452.1813 (M+H)⁺, found 452.1821.

Example 33

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2,4-difluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃) for the most potent isomer: δ 2.32-2.41 (1H),2.62-2.72 (1H), 2.85-2.93 (1H), 3.89-3.96 (1H), 4.20 (1H), 4.26-4.37(2H), 4.66-4.73 (1H), 5.74 (1H), 6.81-6.95 (2H), 7.26-7.34 (2H),7.37-7.44 (1H), 7.46-7.52 (1H), 7.61-7.66 (1H), 9.01 (1H). HRMS (ES+)calculated for C₂₀H₁₇C1F₂N₆O₄ 479.1046 (M+H), found 479.1059.

Example 34

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2,3-difluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 8.97 (s, 1H), 7.62 (d, 1H), 7.47 (dd, 1H),7.33 (br. t, 1H), 7.29 (d, 1H), 7.18-7.03 (m, 3H), 5.78 (s, 1H), 4.67(dd, 1H), 4.36-4.24 (m, 2H), 4.16 (br., 1H), 3.94-3.88 (m, 1H),2.91-2.83 (m, 1H), 2.73-2.62 (m, 1H), 2.40-2.30 (m, 1H), HRMS (ESI)calculated for C₂₀H₁₇ClF₂N₆O₄ 479.1046 (M+H)⁺, found 479.1053.

Example 35

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(3,5-difluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide

¹H NMR (400 MHz, CDCl₃) for the most potent isomer: δ 8.96 (s, 1H), 7.62(d, 1H), 7.48 (dd, 1H), 7.31 (br. t, 1H), 7.28 (d, 1H), 6.96-6.89 (m,2H), 6.81-6.73 (m, 1H), 5.49 (d, 1H), 4.64 (dd, 1H), 4.36-4.25 (m, 2H),4.21 (d, 1H), 4.03-3.97 (m, 1H), 3.14-3.05 (m, 1H), 2.76-2.66 (m, 1H),2.42-2.32 (m, 1H), HRMS (ESI) calculated for C₂₀H₁₇ClF₂N₆O₄ 479.1046(M+H)⁺, found 479.1030.

Example 36

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2-fluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide

¹H NMR (600 MHz, CDCl₃): δ 2.27-2.35 (1H), 2.60-2.68 (1H), 2.70-2.77(1H), 3.81-3.87 (1H), 4.24-4.34 (2H), 4.65-4.70 (1H), 5.76 (1H),7.04-7.10 (1H), 7.11-7.16 (1H), 7.26-7.34 (4H), 7.45-7.50 (1H),7.59-7.62 (1H), 8.96 (1H). HRMS (ES+) calculated for C₂₀H₁₈ClFN₆O₄461.1140 (M+H)⁺, found 461.1151.

Example 37

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[hydroxy(3-methylphenyl)acetyl]isoxazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃) for the most potent isomer: δ 9.02 (s, 1H), 7.60(d, 1H), 7.47 (br. t, 1H), 7.44 (dd, 1H), 7.24-7.09 (m, 5H), 5.45 (d,1H), 4.64 (dd, 1H), 4.34-4.21 (m, 2H), 4.14 (d, 1H), 3.85-3.78 (m, 1H),2.76-2.67 (m, 1H), 2.62-2.51 (m, 1H), 2.32 (s, 3H), 2.32-2.22 (m, 1H),HRMS (ESI) calculated for C₂₁H₂₁ClN₆O₄ 457.1391 (M+H)⁺, found 457.1390.

Example 38

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxyhexanoyl]isoxazolidine-3-carboxamide

¹H NMR (600 MHz, CDCl₃): δ 0.86-0.92 (3H), 1.23-1.54 (5H), 1.58-1.66(1H), 2.47-2.55 (1H), 2.77-2.84 (1H), 3.22 (1H), 3.85-3.91 (1H),4.16-4.22 (1H), 4.22-4.31 (2H), 4.47-4.52 (1H), 4.69-4.74 (1H),7.24-7.26 (1H), 7.42-7.45 (1H), 7.50-7.56 (1H), 7.57-7.60 (1H), 9.00(1H). HRMS (ES+) calculated for C₁₈H₂₃ClN₆O₄ 423.1548 (M+H)⁺, found423.1535.

Example 39

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-5-methylhexanoyl]isoxazolidine-3-carboxamide

¹H NMR (600 MHz, CDCl₃): δ 0.84-0.92 (6H), 1.24-1.40 (2H), 1.47-1.69(3H), 2.46-2.55 (1H), 2.81-2.89 (1H), 3.11 (1H), 3.86-3.93 (1H),4.17-4.33 (3H), 4.48-4.53 (1H), 4.69-4.75 (1H), 7.26-7.28 (1H),7.42-7.48 (2H), 7.57-7.60 (1H), 8.96 (1H). HRMS (ES+) calculated forC₁₉H₂₅ClN₆O₄ 437.1704 (M+H)⁺, found 437.1715.

Example 40

(3S)-2-[(2R)-3-tert-Butoxy-2-hydroxypropanoyl]-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]isoxazolidine-3-carboxamide

¹H NMR (600 MHz, CDCl₃): δ 1.14 (9H), 2.45-2.54 (1H), 2.74-2.83 (1H),3.51-3-57 (1H), 3.64-3.69 (1H), 3.92-3.99 (1H), 4.13-4.19 (1H),4.21-4.31 (2H), 4.65-4.70 (1H), 4.73-4.79 (1H), 7.24-7.28 (1H),7.42-7.46 (1H), 7.48-7.54 (1H), 7.56-7.60 (1H), 9.00 (1H). HRMS (ES+)calculated for C₁₉H₂₅ClN₆O₅ 453.1653 (M+H)⁺, found 423.1571.

Example 41

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-cyclopentyl-2-hydroxyacetyl]isoxazolidine-3-carboxamide

¹H NMR (600 MHz, CDCl₃): δ 1.40-1.72 (8H), 2.12-2.20 (1H), 2.46-2.55(1H), 2.80-2.90 (1H), 3.87-3.94 (1H), 4.16-4.31 (3H), 4.49-4.52 (1H),4.70-4.75 (1H), 7.26-7.28 (1H), 7.43-7.47 (1H), 7.52-7.60 (2H), 8.99(1H). HRMS (ES+) calculated for C₁₉H₂₃ClN₆O₄ 435.1548 (M+H)⁺, found435.1559.

Example 42

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-cyclohexyl-2-hydroxyacetyl]isoxazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 8.99 (s, 1H), 7.59 (d, 1H), 7.57 (br. t, 1H),7.45 (dd, 1H), 7.27 (m, 1H), 4.73 (dd, 1H), 4.37 (d, 1H), 4.27 (m, 2H),4.20 (m, 1H), 3.89 (q, 1H), 2.85 (m, 1H), 2.51 (m, 1H), 1.82-1.70 (m,2H), 1.69-1.53 (m, 3H), 1.52-1.42 (m, 1H), 1.41-1.30 (m, 1H), 1.29-1.07(m, 4H). HRMS (ESI) calculated for C₂₀H₂₆ClN₆O₄ 449.1704 (M+H)⁺, found449.1725.

Example 43

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3-(1-methylcyclopropyl)propanoyl]isoxazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 9.02 (s, 1H), 7.60 (d, 1H), 7.57 (bt, 1H),7.44 (dd, 1H), 7.26 (d, 1H), 4.66-4.72 (m, 2H), 4.23-4.33 (m, 2H), 4.18(ddd, 1H), 3.92 (q, 1H), 3.17 (d, 1H), 2.77-2.85 (m, 1H), 2.46-2.54 (m,1H), 1.60 (dd, 1H), 1.38 (dd, 1H), 1.13 (s, 3H), 0.21-0.45 (m, 4H). HRMS(ESI) calculated for C₁₉H₂₄ClN₆O₄ 435.1548 (M+H)⁺, found 435.1535.

Example 44

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-2-phenylacetyl]isoxazolidine-3-carboxamide

¹H NMR (400 MHz, CDCl₃): δ 9.02 (s, 1H), 7.61 (d, 1H), 7.47 (bt, 1H),7.44 (dd, 1H), 7.12-7.35 (m, 6H), 5.49 (d, 1H), 4.64 (dd, 1H), 4.22-4.33(m, 2H), 4.20 (d, 1H), 3.81 (ddd, 1H), 2.64-2.72 (m, 1H), 2.52-2.62 (m,1H), 2.22-2.31 (m, 1H). HRMS (ESI) calculated for C₂₀H₂₀ClN₆O₄ 443.1234(M+H)⁺, found 443.1234.

Example 45

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]isoxazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 9.04 (s, 1H), 7.73 (bt, 1H), 7.58 (d, 1H),7.42 (dd, 1H), 7.25 (d, 1H), 4.75 (dd, 1H), 4.22-4.30 (m, 3H), 4.11-4.17(ddd, 1H), 3.97 (q, 1H), 3.12 (bs, 1H), 2.77-2.88 (m, 1H), 2.40-2.50 (m,1H), 0.94 (s, 9H). HRMS (ESI) calculated for C₁₈H₂₄ClN₆O₄ 423.1548(M+H)⁺, found 423.1552.

Example 46

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-4,4-dimethylpentanoyl]isoxazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 8.97 (s, 1H), 7.59 (d, 1H), 7.44-7.50 (m,2H), 7.27 (d, 1H), 4.69 (dd, 1H), 4.63 (dd, 1H), 4.27 (d, 2H), 4.18(ddd, 1H), 3.93 (q, 1H), 2.80-2.88 (m, 1H), 2.47-2.55 (m, 1H), 1.40 (d,2H), 1.01 (s, 9H). HRMS (ESI) calculated for C₁₉H₂₆ClN₆O₄ 437.1704(M+H)⁺, found 437.1700.

Example 47

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3-phenylpropanoyl]isoxazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 8.97 (s, 1H), 7.59 (d, 1H), 7.48 (dd, 1H),7.45 (bt, 1H), 7.20-7.35 (m, 6H), 4.85 (ddd, 1H), 4.66 (dd, 1H),4.24-4.34 (m, 2H), 4.06 (ddd, 1H), 3.40 (q, 1H), 3.23 (d, 1H), 3.02 (dd,1H), 2.97 (dd, 1H), 2.76-2.84 (m, 1H), 2.32-2.40 (m, 1H). HRMS (ESI)calculated for C₂₁H₂₂ClN₆O₄ 457.1391 (M+H)⁻, found 457.1394.

Example 48

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(3-cyanophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide

¹H NMR (400 MHz, CDCl₃) for the most potent isomer: δ 8.95 (s, 1H),7.60-7.70 (m, 4H), 7.45-7.52 (m, 2H), 7.25-7.31 (m, 2H), 5.54 (s, 1H),4.63 (dd, 1H), 4.31 (d, 2H), 3.97 (ddd, 1H), 2.98 (ddd, 1H), 2.70 (dddd,1H), 2.34 (dddd, 1H). HRMS (ESI) calculated for C₂₁H₁₉ClN₇O₄ 468.1187(M+H)⁺, found 468.1223.

Example 49

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-2-phenylacetyl]pyrazolidine-3-carboxamide(i) tert-Butyl2-[(1S)-3-bromo-1-(ethoxycarbonyl)propyl]hydrazinecarboxylate

To a solution of ethyl(2R)-4-bromo-2-hydroxybutanoate (1.1 g, 5.2 mmol,prepared as described in J. Med. Chem. 2003, 46, 2057 or J. Am. Chem.Soc., 2004, 126, 12432 and Tetrahedron Letters 1997, 38, 4935-4938, indry DCM (20 mL) at 0° C. was added Tf₂O (1.62 g, 5.7 mmol) via syringe.After 5 min, 2,6-lutidine (0.67 g, 6.2 mmol) was added. After another 5min, t-butylcarbazate (1.38 g, 10.4 mmol) in DCM (5 mL) was added. Thesolution was allowed to attain rt and stirred overnight. The solvent wasevaporated and the residue was purified using flash chromatography(heptane/EtOAc 4:1, 3:1, 2:1) to give the slightly impure tert-butyl2-[(1S)-3-bromo-1-(ethoxycarbonyl)propyl]hydrazinecarboxylate (1.65 g,97%) as an oil.

(ii) 1-tert-Butyl 3-ethyl(3S)-pyrazolidine-1,3-dicarboxylate

To a solution of slightly impure tert-butyl2-[(1S)-3-bromo-1-(ethoxycarbonyl)propyl]hydrazinecarboxylate (1.57 g,4.83 mmol) in dry THF (50 mL) at 0° C. was added LiHMDS (1 M in THF,4.83 mmol, 4.83 mL) The solution was allowed to attain rt and was thenstirred for 2 h. The reaction was quenched by addition of saturatedNH₄Cl (aq) and diluted with TBME. The phases were separated, the organicphase was dried, filtered and evaporated. The residue was purified usingflash chromatography (DCM/EtOAc 4:1, 1:1) to give the pure 1-tert-butyl3-ethyl(3S)-pyrazolidine-1,3-dicarboxylate (610 mg, 52%) as an oil.

1HNMR (CDCl₃) 500 MHz: δ 1.30 (t, 3H), 1.51 (s, 9H), 2.13 (m, 1H), 2.41(m, 1H), 3.48 (m, 1H), 3.65 (m, 1H), 3.88 (t, 1H), 4.24 (m, 2H), 4.55(bs, 1H).

(iii)tert-Butyl(3S)-3-{[5-chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}pyrazolidine-1-carboxylate

To a solution of (S)-pyrazolidine-1,3-dicarboxylic acid 1-tert-butylester 3-ethyl ester (1.920 g, 7.86 mmol) in THF (60 mL) was added asolution of lithium hydroxide (188 mg, 7.86 mmol in 20 mL water) and themixture was stirred at rt for 1 h. The solvents were evaporated and thesolid residue was suspended in DCM (70 mL) To this suspension was added5-chloro-2-tetrazol-1-yl-benzylamine hydrochloride (2.13 g, 8.645 mmol,prepared as described in J. Med. Chem. 2004, 47, 2995),hydroxybenzotriazole (1.17 g, 8.645 mmol, as a solution in 10 mL DMF),followed by EDC (2.26 g, 11.79 mmol) and triethylamine (0.795 mg, 7.895mmol). The resulting mixture was stirred at rt for 3 h and was thendiluted with EtOAc and washed with 1 M HCl, saturated NaHCO₃(aq) andbrine. The organic phase was dried, filtered, evaporated and purifiedusing flash chromatography (EtOAc, then EtOAc/MeOH gradient from 20:1 to10:1) to givetert-butyl(3S)-3-{[5-chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}pyrazolidine-1-carboxylate(2.05 g, 64%) as an oil.

(iv)(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-2-phenylacetyl]pyrazolidine-3-carboxamide

To a solution oftert-butyl(3S)-3-{[5-chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}pyrazolidine-1-carboxylate(82 mg, 0.200 mmol) in DCM (2 mL) and pyridine (0.080 mL) was added asolution of (R)-2-phenyl-2-(trimethylsilyloxy)acetyl chloride (ca 0.3 Min DCM, 1 mL, 0.3 mmol, see Preparation 2). The resulting solution wasstirred at rt over night. TFA (ca 1 mL) was added and the mixture wasstirred for one more hour and then evaporated. The residue was purifiedusing flash chromatography (DCM/MeCN gradient from 2:1 to 1:1) to give(3S)—N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-2-phenylacetyl]pyrazolidine-3-carboxamide(52 mg, 59%) as an oil.

¹H NMR (500 MHz, CDCl₃): δ 9.04 (s, 1H), 7.69 (bt, 1H), 7.61 (d, 1H),7.45 (dd, 1H), 7.35-7.38 (m, 2H), 7.25-7.33 (m, 4H), 5.61 (d, 1H), 4.51(d, 1H), 4.42 (t, 1H), 4.35 (dd, 1H), 4.18-4.26 (m, 2H), 3.01-3.08 (m,1H), 2.25-2.35 (m, 1H), 2.14-2.17 (m, 2H). HRMS (ESI) calculated forC₂₀H₂₁ClN₇O₃ 442.1394 (M+H)⁺, found 442.1418.

Examples 50-57 were prepared in a manner analogous to Example 49described above using the appropriate starting materials.

Example 50

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2-fluorophenyl)(hydroxy)acetyl]pyrazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃) for the most potent isomer: δ 9.04 (s, 1H),7.65-7.58 (m, 2H), 7.45 (dd, 1H), 7.30-7.18 (m, 3H), 7.07 (t, 1H), 7.01(dd, 1H), 5.78 (s, 1H), 4.47 (dd, 1H), 4.36 (dd, 1H), 4.22 (dd, 1H),4.14 (br. d, 1H), 2.96 (br. dd, 1H), 2.31 (m, 1H), 2.13 (m, 1H),1.96-1.81 (m, 1H). HRMS (ESI) calculated for C₂₀H₂₀Cl FN₇O₃ 460.1300(M+H)⁺, found 460.1314.

Example 51

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2,4-difluorophenyl)(hydroxy)acetyl]pyrazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃) for the most potent isomer: δ 9.03 (s, 1H), 7.62(d, 1H), 7.55 (bt, 1H), 7.48 (dd, 1H), 7.30 (d, 1H), 7.22 (ddd, 1H),6.76-6.86 (m, 2H), 5.75 (s, 1H), 4.48 (t, 1H), 4.39 (dd, 1H), 4.30 (bs,1H), 4.23 (dd, 1H), 4.16 (dd, 1H), 3.02 (ddd, 1H), 2.32-2.40 (m, 1H),2.13-2.20 (m, 1H), 1.87-1.97 (m, 1H). HRMS (ESI) calculated forC₂₀H₁₉ClF₂N₇O₃ 478.1206 (M+H)⁺, found 478.1201.

Example 52

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]pyrazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃) for the most potent isomer: δ 9.00 (s, 1H), 7.62(d, 1H), 7.55 (bt, 1H), 7.48 (dd, 1H), 7.35-7.40 (m, 2H), 7.30 (d, 1H),6.96-7.03 (m, 2H), 5.62 (d, 1H), 4.37-4.45 (m, 2H), 4.21 (dd, 1H), 3.08(dd, 1H), 2.30-2.44 (m, 1H), 2.05-2.20 (m, 2H). HRMS (ESI) calculatedfor C₂₀H₂₀ClFN₇O₃ 460.1300 (M+H)⁺, found 460.1302.

Example 53

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(4-hydroxy-3,4-dihydro-2H-chromen-4-yl)carbonyl]pyrazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃) for the most potent isomer: δ 9.05 (s, 1H), 7.69(d, 1H), 7.45-7.55 (m, 2H), 7.30 (d, 1H), 7.10-7.17 (m, 1H), 6.67-6.85(m, 3H), 5.12 (bs, 1H), 4.56 (dd, 1H), 4.15-4.45 (m, 4H), 3.35-3.42 (m,1H), 3.12-3.22 (m, 1H), 2.60-2.80 (m, 2H), 2.20-2.40 (m, 2H), 1.94 (dt,1H). HRMS (ESI) calculated for C₂₂H₂₃ClN₇O₄ 484.1500 (M+H)⁺, found484.1503.

Example 54

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-4,4-dimethylpentanoyl]pyrazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 9.02 (s, 1H), 7.64 (bt, 1H), 7.59 (d, 1H),7.46 (dd, 1H), 7.28 (d, 1H), 4.69 (dd, 1H), 4.52 (t, 1H), 4.40 (dd, 1H),4.18 (dd, 1H), 3.33 (dd, 1H), 2.75 (ddd, 1H), 2.46-2.56 (m, 1H),2.27-2.37 (m, 1H), 1.46 (dd, 1H), 1.35 (dd, 1H), 1.01 (s, 9H). HRMS(ESI) calculated for C₁₉H₂₇ClN₇O₃ 436.1864 (M+H)⁺, found 436.1881.

Example 55

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-cyclohexyl-2-hydroxyacetyl]pyrazolidine-3-carboxamide

¹H NMR (500 MHz, CD₃OD): δ 9.54 (s, 1H), 7.72 (d, 1H), 7.55 (dd, 1H),7.48 (d, 1H), 4.38-4.43 (m, 2H), 4.25 (s, 2H), 3.23 (ddd, 1H), 2.73(ddd, 1H), 2.41-2.48 (m, 1H), 1.95-2.03 (m, 1H), 1.50-1.80 (m, 6H),1.06-1.32 (m, 5H). HRMS (ESI) calculated for C₂₀H₂₇ClN₇O₃ 448.1864(M+H)⁺, found 448.1859.

Example 56

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3-phenylpropanoyl]pyrazolidine-3-carboxamide

¹H NMR (500 MHz, CD₃OD): δ 9.53 (s, 1H), 7.70 (d, 1H), 7.54 (dd, 1H),7.47 (d, 1H), 7.05-7.28 (m, 5H), 4.93 (dd, 1H), 4.35 (t, 1H), 4.24 (s,2H), 3.10-3.17 (m, 1H), 3.01 (dd, 1H), 2.79 (dd, 1H), 2.32-2.46 (m, 2H),1.90-2.00 (m, 1H). HRMS (ESI) calculated for C₂₁H₂₃ClN₇O₃ 456.1551(M+H)⁺, found 456.1531.

Example 57

(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]pyrazolidine-3-carboxamide

¹H NMR (500 MHz, CDCl₃): δ 9.03 (s, 1H), 7.68 (bt, 1H), 7.59 (d, 1H),7.47 (dd, 1H), 7.28 (d, 1H), 4.62 (dd, 1H), 4.46 (dd, 1H), 4.37 (d, 1H),4.28 (dd, 1H), 4.10-4.25 (m, 2H), 3.30-3.37 (m, 1H), 2.78-2.88 (m, 1H),2.54-2.64 (m, 1H), 2.25-2.33 (m, 1H), 0.97 (s, 9H). HRMS (ESI)calculated for C₁₈H₂₅ClN₇O₃ 422.1707 (M+H)⁻, found 422.1708.

Biological Tests

The following test procedures may be employed:

Test A

Determination of Thrombin Inhibition with a Chromogenic, Robotic Assay

The thrombin inhibitor potency is measured with a chromogenic substratemethod, in a Plato 3300 robotic microplate processor (Rosys AG, CH-8634Hombrechtikon, Switzerland), using 96-well, half volume microtitreplates (Costar, Cambridge, Mass., USA; Cat No 3690). Stock solutions oftest substance in DMSO (72 μL), 0.1-1 mmol/L, are diluted serially 1:3(24+48 μL) with DMSO to obtain ten different concentrations, which areanalyzed as samples in the assay. 2 μL of test sample is diluted with124 μL assay buffer, 12 μL of chromogenic substrate solution (S-2366,Chromogenix, Mölndal, Sweden) in assay buffer and finally 12 μL ofα-thrombin solution (Human α-thrombin, Sigma Chemical Co. or HematologicTechnologies) in assay buffer, are added, and the samples mixed. Thefinal assay concentrations are: test substance 0.00068-133 μmol/L,S-2366 0.30 mmol/L, α-thrombin 0.020 NIHU/mL The linear absorbanceincrement during 40 minutes incubation at 37° C. is used for calculationof percentage inhibition for the test samples, as compared to blankswithout inhibitor. The IC₅₀ value, corresponding to the inhibitorconcentration which causes 50% inhibition of the thrombin activity, iscalculated from a log concentration vs. % inhibition curve.

Test B

Determination of Activated Partial Thromboplastin Time (APTT)

APTT is determined in pooled normal human citrated plasma with thereagent PTT Automated 5 manufactured by Stago. The inhibitors are addedto the plasma (10 μL, inhibitor solution to 90 μL, plasma) and incubatedwith the APTT reagent for 3 minutes followed by the addition of 100 μL,of calcium chloride solution (0.025 M) and APTT is is determined by useof the coagulation analyzer KC10 (Amelung) according to the instructionsof the reagent producer.

The clotting time is expressed as absolute values (seconds) as well asthe ratio of APTT without inhibitor (APTT₀) to APTT with inhibitor(APTT_(i)). The latter ratios (range 1-0) are plotted against theconcentration of inhibitor (log transformed) and fitted to sigmoidaldose-response curves according to the equation

y=a/[1+(x/IC ₅₀)^(s)]

where: a=maximum range, i.e. 1; s=slope of the dose-response curve; andIC₅₀=the concentration of inhibitor that doubles the clotting time. Thecalculations are processed on a PC using the software program GraFitVersion 3, setting equation equal to: Start at 0, define end=1(Erithacus Software, Robin Leatherbarrow, Imperial College of Science,London, UK).

IC₅₀APTT is defined as the concentration of inhibitor in human plasmathat doubled the Activated Partial Thromboplastin Time.

Results

Compounds of the Examples were tested in Test A as described above andwere found to exhibit IC₅₀ values of less than 1 μM. The following tableshows the IC₅₀ values for a representative selection of compounds:

Test A Example IC₅₀ No. (nM) 1 4 2 34 3 22 4 18 5 24 6 35 7 5.7 8 5.8 932 10 11 11 21 12 130 13 7.8 14 8.5 15 6.3 16 44 17 20 18 3.5 19 31 2028 21 25 22 740 23 193 24 140 25 160 26 150 27 140 28 120 29 13 30 66031 9.7 32 170 33 100 34 160 35 70 36 94 37 16 38 43 39 13 40 44 41 41 4221 43 68 44 26 45 32 46 40 47 80 48 92 49 16 50 79 51 63 52 8.4 53 24054 24 55 8.4 56 79 57 27

1. A compound of formula (I)

wherein X is N, O or NH; Y is CH₂ when X is O or NH, with X and Yconnected via a single bond, or, alternatively, Y is CH when X is N,with X and Y connected via a double bond; R¹ is a 5-membered heteroarylring containing 2, 3 or 4 heteroatoms, selected from N, O and S, whereinat least 2 heteroatoms are N, and 0 or 1 heteroatoms are O or S, whereinsaid 5-membered heteroaryl ring is substituted, at any carbon ring atom,by 0, 1 or 2 substituents independently selected from C₁₋₆ alkyl and a6-membered heteroaryl ring containing 1 or 2 nitrogen atoms, whereinsaid 6-membered heteroaryl ring is substituted, at any carbon ring atom,by 0, 1, 2 or 3 substituents independently selected from C₁₋₆ alkyl; R²is H, halogen, cyano, C₁₋₆ alkyl and C₁₋₆ alkoxy, wherein said C₁₋₆alkyl or C₁₋₆ alkoxy is substituted by 0, 1, 2, 3, 4 or 5 halogen; Grepresents

wherein R³ is H, R⁵, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₃₋₆cycloalkyl, wherein each of said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₃₋₆ cycloalkyl are independently substituted by 0, 1, 2, 3, 4 or 5substituents selected from halogen and 0, 1 or 2 substituents selectedfrom OH, oxo, cyano, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₄₋₇ cycloalkenyl, cycloheteroalkyl, R⁵ and R⁶; R⁵ isphenyl, a 5 or 6-membered heteroaromatic ring containing 1, 2 or 3heteroatoms independently selected from O, S and N, a 4-, 5- or6-membered cycloheteroalkyl ring containing 1 or 2 heteroatomsindependently selected from O, S and N or a phenyl-fused 5- or6-membered cycloheteroalkyl ring containing 1 or 2 heteroatomsindependently selected from O, S and N, wherein said phenyl, saidheteroaromatic ring, said cycloheteroalkyl ring and said phenyl-fusedcycloheteroalkyl ring are substituted, at any carbon ring atom, by 0, 1,2, 3, 4 or 5 substituents independently selected from COOH, OH, halogen,CF₃, CHF₂, CH₂F, cyano, C₁₋₆ alkyl, R⁶ and SO₂R⁷; R⁶ is C₁₋₆ alkoxy,wherein said C₁₋₆ alkoxy is substituted by 0, 1, 2, 3, 4 or 5 halogen;R⁷ is C₁₋₆ alkyl; R⁴ is OH, OC(O)R⁷, OC(O)R⁸ or NHR⁹; R⁸ is phenyl,wherein said phenyl is substituted by 0, 1, 2, 3, 4 or 5 substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, F, CF₃, CHF₂and CH₂F or C₁₋₄ alkyl, wherein said C₁₋₄ alkyl is substituted by 0, 1,2 or 3 substituents independently selected from methyl and ethyl and 0or 1 substituents selected from phenyl, wherein said phenyl issubstituted by 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, F, CF₃, CHF₂, CH₂F and OC(O)R⁷; R⁹is H, COOR⁷ or SO₂R⁷ wherein said R⁷ is substituted by 0, 1, 2 or 3substituents independently selected from OH, halogen, cyano, R⁶ and C₃₋₇cycloalkyl; Q is O, CH₂ or S(O)_(n); W is C or N; n is independently 0,1 or 2; each t is independently 0, 1 or 2; u is independently 0 or 1;R¹⁰ is 0, 1, 2, 3, 4 or 5 substituents selected from halogen, OH, oxo,cyano, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, R⁵ and R⁶, wherein said C₁₋₄ alkylis substituted by 0 or 1 substituent selected from R⁵, NH₂, NH(C₁₋₄alkyl) or N(C₁₋₄ alkyl)₂; and R¹¹ is 0, 1, 2, 3, 4 or 5 substituentsselected from halogen, OH, cyano, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, R⁵ andR⁶, wherein said C₁₋₄ alkyl is substituted by 0 or 1 substituentselected from R⁵, NH₂, NH(C₁₋₄ alkyl) or N(C₁₋₄ alkyl)₂; or apharmaceutically acceptable salt or an enantiomer or a pharmaceuticallyacceptable salt of said enantiomer.
 2. A compound according to claim 1,wherein G is

or a pharmaceutically acceptable salt or an enantiomer or apharmaceutically acceptable salt of said enantiomer.
 3. A compoundaccording to claim 2, wherein R¹ is a 5-membered heteroaryl ringcontaining 2, 3 or 4 heteroatoms, selected from N, O and S, wherein atleast 2 heteroatoms are N, and 0 or 1 heteroatoms are O or S; R² is H orhalogen; R³ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, a 5 or 6-memberedheteroaromatic ring containing 1, 2 or 3 heteroatoms independentlyselected from O, S and N, a 4-, 5- or 6-membered cycloheteroalkyl ringcontaining 1 or 2 heteroatoms independently selected from O, S and N, orR¹², wherein said C₁₋₆ alkyl, said C₃₋₆ cycloalkyl, said heteroaromaticring and said cycloheteroalkyl ring are substituted by 0 or 1substituents selected from NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₃cycloalkyl, R⁶ or R¹²; R¹² is phenyl, wherein said phenyl is substitutedby 0, 1 or 2 substituents selected from halogen and R⁶; and R⁴ is OH,OC(O)R⁷, OC(O)R⁸ or NH₂; or a pharmaceutically acceptable salt or anenantiomer or a pharmaceutically acceptable salt of said enantiomer. 4.A compound according to claim 3, wherein R¹ is tetrazole; R² is H, Cl orF; R³ is C₃₋₆ cycloalkyl, R¹² or C₁₋₆ alkyl, wherein said C₁₋₆ alkyl issubstituted by 0 or 1 substituents selected from C₃ cycloalkyl, N(C₁₋₄alkyl)₂, R⁶ or R¹²; and R⁴ is OH or OC(O)R⁷; or a pharmaceuticallyacceptable salt or an enantiomer or a pharmaceutically acceptable saltof said enantiomer.
 5. A compound according to claim 3, wherein thestereochemical configuration around the carbon in the pyrazolidine,dihydropyrazole or isoxazolidine, i.e. the ring containing X and Y,which is covalently bound to the carbonyl is (S) and the stereochemicalconfiguration around the carbon substituted by R³ and R⁴ in G is (R); ora pharmaceutically acceptable salt or an enantiomer or apharmaceutically acceptable salt of said enantiomer.
 6. A compoundaccording to claim 1, wherein G is

or a pharmaceutically acceptable salt or an enantiomer or apharmaceutically acceptable salt of said enantiomer.
 7. A compoundaccording to claim 6, wherein R¹ is a 5-membered heteroaryl ringcontaining 2, 3 or 4 heteroatoms, selected from N, O and S, wherein atleast 2 heteroatoms are N, and 0 or 1 heteroatoms are O or S; R² is H orhalogen; Q is O or CH₂; each t is independently 0 or 1; R¹⁰ is 0, 1 or 2substituents selected from oxo, C₁₋₄ alkyl, R⁵ and R⁶; and R⁵ is phenyl,which is substituted, by 0, 1, 2, 3, 4 or 5 substituents independentlyselected from COOH, OH, halogen, CF₃, cyano, C₁₋₆ alkyl, R⁶ and SO₂R⁷;or a pharmaceutically acceptable salt or an enantiomer or apharmaceutically acceptable salt of said enantiomer.
 8. A compoundaccording to claim 7, wherein R¹ is tetrazole; R² is H, Cl or F; and R¹⁰is 0, 1 or 2 substituents selected from oxo and C₁₋₄ alkyl; or apharmaceutically acceptable salt or an enantiomer or a pharmaceuticallyacceptable salt of said enantiomer.
 9. A compound according to claim 1,wherein G is

or a pharmaceutically acceptable salt or an enantiomer or apharmaceutically acceptable salt of said enantiomer.
 10. A compoundaccording to claim 9, wherein R¹ is a 5-membered heteroaryl ringcontaining 2, 3 or 4 heteroatoms, selected from N, O and S, wherein atleast 2 heteroatoms are N, and 0 or 1 heteroatoms are O or S; R² is H orhalogen; R⁴ is OH, OC(O)R⁷, OC(O)R⁸ or NH₂; Q is O or CH₂; u isindependently 0 or 1; R¹⁰ is 0, 1 or 2 substituents selected from C₁₋₄alkyl, halogen and R⁶; and R¹¹ is 0, 1 or 2 substituents selected fromC₁₋₄ alkyl, halogen and R⁶; or a pharmaceutically acceptable salt or anenantiomer or a pharmaceutically acceptable salt of said enantiomer. 11.A compound according to claim 10, wherein R¹ is tetrazole; R² is Cl; R⁴is OH or OC(O)R⁷; R¹⁰ is 0, 1 or 2 substituents selected from C₁₋₄alkyl, F, Cl, OCH₃, OCF₃, OCHF₂ and OCH₂F; and R¹¹ is 0, 1 or 2substituents selected from C₁₋₄ alkyl, F, Cl, OCH₃, OCF₃, OCHF₂ andOCH₂F; or a pharmaceutically acceptable salt or an enantiomer or apharmaceutically acceptable salt of said enantiomer.
 12. A compoundaccording to claim 7, wherein the stereochemical configuration aroundthe carbon in the pyrazolidine, dihydropyrazole or isoxazolidine, i.e.the ring containing X and Y, which is covalently bound to the carbonylis (S); or a pharmaceutically acceptable salt or an enantiomer or apharmaceutically acceptable salt of said enantiomer.
 13. A compoundaccording to claim 3, wherein X is NH and Y is CH₂, with X and Yconnected via a single bond; or a pharmaceutically acceptable salt or anenantiomer or a pharmaceutically acceptable salt of said enantiomer. 14.A compound according to claim 3, wherein X is O and Y is CH₂, with X andY connected via a single bond; or a pharmaceutically acceptable salt oran enantiomer or a pharmaceutically acceptable salt of said enantiomer.15. A compound according to claim 3, wherein X is N and Y is CH, with Xand Y connected via a double bond; or a pharmaceutically acceptable saltor an enantiomer or a pharmaceutically acceptable salt of saidenantiomer.
 16. A compound according to claim 1 which is selected from(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2,3-difluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)-1-[(2R)-3-tert-Butoxy-2-hydroxypropanoyl]-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(3,5-difluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-cyclopentyl-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2,4-difluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-2-(3-methylphenyl)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-5-methylhexanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2-fluorophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxyhexanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3-(1-methylcyclopropyl)propanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(4-hydroxy-3,4-dihydro-2H-chromen-4-yl)carbonyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-2-phenylacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-4,4-dimethylpentanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-cyclohexyl-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3-methoxy-3-methylbutanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3-phenylpropanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-(4-methyl-D-leucyl)-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-3-cyclopropyl-2-hydroxypropanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(3-cyanophenyl)(hydroxy)acetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,(5S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2S)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide,[(1R)-2-[(5S)-5-[[5-Chloro-2-(tetrazol-1-yl)phenyl]methylcarbamoyl]-4,5-dihydropyrazol-1-yl]-1-(4-fluorophenyl)-2-oxo-ethyl]acetate,(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethyl3-methylbutanoate,(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethylbutanoate,(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethyl2-methylpropanoate,(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethylpentanoate,(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethylpropanoate,(1R)-2-[(5S)-5-{[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}-4,5-dihydro-1H-pyrazol-1-yl]-1-(4-fluorophenyl)-2-oxoethylbenzoate,(R)-2-((S)-5-(5-Chloro-2-(1H-tetrazol-1-yl)benzylcarbamoyl)-4,5-dihydro-1H-pyrazol-1-yl)-1-(4-fluorophenyl)-2-oxoethyl3-(2,4-dimethyl-6-(propionyloxy)phenyl)-3-methylbutanoate,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]isoxazolidine-3-carboxamide,(3S)-2-(O-tert-Butyl-D-seryl)-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2,4-difluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2,3-difluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(3,5-difluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2-fluorophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[hydroxy(3-methylphenyl)acetyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxyhexanoyl]isoxazolidine-3-carboxamide,3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-5-methylhexanoyl]isoxazolidine-3-carboxamide,(3S)-2-[(2R)-3-tert-Butoxy-2-hydroxypropanoyl]-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-cyclopentyl-2-hydroxyacetyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-cyclohexyl-2-hydroxyacetyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3-(1-methylcyclopropyl)propanoyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-2-phenylacetyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-4,4-dimethylpentanoyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3-phenylpropanoyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(3-cyanophenyl)(hydroxy)acetyl]isoxazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-2-phenylacetyl]pyrazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2-fluorophenyl)(hydroxy)acetyl]pyrazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2,4-difluorophenyl)(hydroxy)acetyl]pyrazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]pyrazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(4-hydroxy-3,4-dihydro-2H-chromen-4-yl)carbonyl]pyrazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-4,4-dimethylpentanoyl]pyrazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-cyclohexyl-2-hydroxyacetyl]pyrazolidine-3-carboxamide,(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3-phenylpropanoyl]pyrazolidine-3-carboxamideor(3S)—N-[5-Chloro-2-(1H-tetrazol-1-yl)benzyl]-2-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]pyrazolidine-3-carboxamide;or a pharmaceutically acceptable salt or an enantiomer or apharmaceutically acceptable salt of said enantiomer.
 17. Apharmaceutical formulation comprising a compound of formula (I)according to claim 1 in admixture with at least one pharmaceuticallyacceptable carrier, excipient or diluent. 18-23. (canceled)
 24. A methodof treatment of a condition where inhibition of thrombin is beneficial,which method comprises administration of a therapeutically effectiveamount of a compound as defined in claim 1 to a person suffering from,or susceptible to, such a condition.
 25. A method of treatment andprevention of thromboembolic disorders, which method comprisesadministration of a therapeutically effective amount of a compound asdefined in claim 1 to a person suffering from, or susceptible to,thrombophilia conditions.